Inclusion Criteria:
* Stage IIIB, IIIC, IIID histologically-proven melanoma.
* Cancer confirmed to be surgically resectable, with surgery evaluation with planned prior to resection.
* No prior immunotherapy with cytotoxic T-lymphocyte associated protein-4 (CTLA-4), anti programmed cell death-1 (PD-1) or VX15/2503. Prior interferon (at least 1 year prior to consent) will be allowed.
* Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1.
* Absolute neutrophil count ≥ 1,500 cells/µL.
* Platelets ≥ 100,000/µL.
* Hemoglobin ≥ 9.0g/dL (may receive packed red blood cells \[PRBC\] transfusion).
* Total bilirubin ≤ 1.5 x the upper limit of normal (ULN).
* Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x ULN.
* Albumin ≥ 3.0 g/dL.
* Serum creatinine ≤ 1.5 x ULN OR calculated creatinine clearance of ≥ 50 mL/min using Cockcroft-Gault formula.
* International normalized ration (INR) ≤ 1.5. Anticoagulation is allowed only with low molecular weight heparin (LMWH). Patient receiving LMW heparin on stable therapeutic dose for more than 2 weeks or with factor Xa level \< 1.1 U/mL are allowed on the trial.
* Willingness and ability to comply with scheduled visits, treatment plans, laboratory tests, and other study procedures.
* Ability to understand and willingness to sign a written informed consent document.
* Female subjects of childbearing potential must agree to use adequate contraception (at least one highly effective method and one additional method of birth control at the same time or complete abstinence) prior to study entry, for the duration of study treatment and 5 months after last dose of study treatment.
* Male subjects must agree to use adequate contraception (at least one highly effective method and one additional method of birth control at the same time or complete abstinence) prior to study entry, for the duration of study treatment and 7 months after last dose of study treatment.
* Female subjects of childbearing age must have a negative serum pregnancy test at study entry.
Exclusion Criteria:
* Determined not to be a surgical candidate due to medical co-morbidities.
* Treatment with chronic immunosuppressants (e.g., cyclosporine following transplantation).
* Prior organ allograft or allogeneic bone marrow transplantation.
* Subjects with active or history of immune mediated pneumonitis, colitis, hepatitis, endocrinopathy, nephritis, or skin reactions as these patients may be at increased risk for developing immune therapy-induced exacerbation or recurrence of their immune mediated disease, potentially delaying surgery.
* Subjects with a condition requiring systemic treatment with either corticosteroids (\> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration. Inhaled or topical steroids and adrenal replacement doses \> 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease.
* Women who are pregnant or lactating.
* Uncontrolled intercurrent illness including, but not limited to, human immunodeficiency virus (HIV)-positive subjects receiving combination antiretroviral therapy, ongoing or active infection, symptomatic congestive heart failure (NYHA class III or IV), unstable angina pectoris, ventricular arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
* Other medications, or severe acute/chronic medical or psychiatric condition, or laboratory abnormality that may increase the risk associated with study participation or study drug administration, or may interfere with the interpretation of study results, and in the judgment of the investigator would make the subject inappropriate for entry into this study.
* Clinical evidence of bleeding diathesis or coagulopathy.
* Patients with prior malignancies, including pelvic cancer, are eligible if they have been disease free for \> 5 years. Patients with prior non-melanoma skin cancers and in situ carcinomas are eligible provided there was complete removal.
* Active bacterial or fungal infections requiring systemic treatment within 7 days of treatment.
* Use of other investigational drugs (drugs not marked for any indication) within 28 days or at least 5 half-lives (whichever is longer) before study drug administration.
* History of severe hypersensitivity reactions to other monoclonal antibodies.
* Non-oncology vaccines within 28 days prior to or after any dose of ipilimumab.
* Prisoners and subjects who are compulsory detained.
* Patients with rapidly progressive disease.
