Inclusion Criteria:

- Diagnosis of melanoma of a cutaneous origin or unknown primary

- No ocular melanoma or melanoma of mucosal origin

- Stage IIIB, IIIC, or IV (M1a or M1b) disease

- Patients with stage IV melanoma must have normal LDH and distant skin,
subcutaneous, lymph node, or lung metastases

- No other visceral metastases allowed

- Disease that has been completely resected with negative margins on resected specimens
within the past 12 weeks

- Disease-free status documented by a complete physical examination and imaging
studies within 4 weeks prior to randomization

- Imaging studies must include a total body PET-CT scan (with or without
brain) and brain MRI or CT (if MRI is contraindicated) (if PET-CT cannot be
done, CT scan of neck, chest, abdomen, and pelvis should be done)

- Patients rendered free of disease by non-surgical means not allowed

- Disease recurrence after adequate surgical excision of original primary cutaneous
melanoma allowed provided one of the following criteria are met:

- Recurrence in a regional lymph node basin after a prior complete lymph node
dissection

- Relapsed disease must be completely surgically resected with free margins

- Recurrence in the form of in-transit or satellite metastases or distant
skin/subcutaneous, nodal, or lung metastases that are completely surgically
resected with free margins

- Recurrence in a regional lymph node basin

- Relapsed disease must be completely surgically resected with free margins

- Patients must be randomized within 84 days (12 weeks) of surgical resection; if more
than one surgical procedure is required to render the patient disease-free, the
patient must be randomized within 12 weeks of the last surgery

- NOTE: patients with clinically positive lymph nodes for melanoma involvement or
those with positive lymph nodes identified through lymphoscintigraphic and/or
dye lymphographic techniques in the groin, axilla, or neck should have
additional lymphadenectomy in those sites; the complete lymph node dissection
procedure would be considered as the last surgery in counting the 84 days unless
a subsequent surgical procedure(s) was clinically required to ensure the disease
free status

- ECOG performance status 0-1

- WBC ≥ 3,000/μL

- ANC ≥ 1,500/μL

- Platelet count ≥ 100,000/μL

- Hemoglobin ≥ 10 g/dL

- Serum creatinine ≤ 1.8 mg/dL

- AST and ALT ≤ 2.5 times upper limit of normal (ULN)

- Serum bilirubin < 2 times ULN (< 3 mg/dL in case of Gilbert syndrome)

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use adequate method of contraception throughout the study and
for up to 26 weeks after the last dose of high-dose recombinant interferon alpha-2b
(HDI)

- No active infection requiring concurrent treatment with parenteral antibiotics

- None of the following:

- Other significant medical, surgical, or psychiatric conditions

- Requirement for any medication or treatment that, in the opinion of the
investigator, may interfere with compliance, make the administration of
ipilimumab or HDI hazardous, or obscure the interpretation of adverse events,
such as a condition associated with frequent diarrhea

- Patients should be carefully screened for depression at baseline and if there are
indications or a history of depression it is strongly recommended that these patients
be closely followed together with behavioral health or psychiatric medical support;
patients with an established diagnosis of depression that, in the assessment of the
investigator may make the administration of IFNα or ipilimumab hazardous, should not
be enrolled on this protocol; the risks and benefits of being treated with standard
adjuvant IFNα should be weighed very carefully in consultation with behavioral health
or psychiatry

- No documented history of inflammatory bowel disease, including ulcerative colitis and
Crohn disease, or diverticulitis

- History of diverticulosis allowed

- No autoimmune disorders or conditions of immunosuppression that require current
ongoing treatment with systemic corticosteroids (or other systemic
immunosuppressants), including oral steroids or continuous use of topical steroid
creams or ointments or ophthalmologic steroids

- History of occasional (but not continuous) use of steroid inhalers allowed

- None of the following:

- History of symptomatic autoimmune disease

- Rheumatoid arthritis

- Systemic progressive sclerosis (scleroderma)

- Systemic lupus erythematosus

- Sjögren syndrome

- Autoimmune vasculitis (e.g., Wegener granulomatosis)

- Motor neuropathy considered of autoimmune origin (e.g., Guillain-Barre syndrome
and myasthenia gravis)

- Other CNS autoimmune disease (e.g., poliomyelitis, multiple sclerosis)

- Autoimmune hypothyroid disease or type 1 diabetes allowed provided replacement
therapy is administered

- Not incarcerated or compulsorily detained (involuntarily incarcerated) for treatment
of either a psychiatric or physical (e.g., infectious) illness

- No other current malignancies except any prior in situ cancer, lobular carcinoma of
the breast in situ, cervical cancer in situ, atypical melanocytic hyperplasia or
melanoma in situ, multiple primary melanomas, basal or squamous skin cancer, or other
malignancies for which the patient has been disease free for > 5 years

- No active or chronic infection with HIV, hepatitis B virus (HBV), or hepatitis C
virus (HCV)

- Patients must have negative testing for HIV, hepatitis B antigen, and HCV within
the past 4 weeks

- No other concurrent anticancer or investigational agent

- No prior adjuvant treatment (chemotherapy, biotherapy, or limb perfusion) after
resection

- At least 30 days since prior radiotherapy, including after surgical resection

- No prior or concurrent anti-CTLA4 monoclonal antibodies, CTLA-4 inhibitor or agonist,
CD137 agonist, or prior interferon-α

- At least 4 weeks since prior aldesleukin (IL-2), anti-tumor vaccine, or chemotherapy
given before randomization

- No infectious disease vaccination (e.g., standard influenza, H1N1 influenza,
pneumococcal, meningococcal, or tetanus toxoid) within the past 4 weeks

- No concurrent systemic corticosteroids (or other systemic immunosuppressants),
including oral steroids (i.e., prednisone, dexamethasone), continuous use of topical
steroid creams or ointments, or ophthalmologic steroids

- Occasional but not continuous use of steroid inhalers allowed

- Systemic corticosteroids (or other systemic immunosuppressants), including oral
steroids (i.e., prednisone, dexamethasone), continuous use of topical steroid
creams or ointments, or ophthalmologic steroids within the past 2 weeks allowed
provided, in judgment of the treating physician investigator, that the patient
is not likely to require resumption of treatment with these classes of drugs
during the study

- Replacement doses of steroids for patients with adrenal insufficiency allowed

- No concurrent chemotherapy or radiotherapy