OBJECTIVE: To review the currently available literature on peginterferon alfa-2b (pegIFN [Sylatron]), including its role in therapy and toxicity for adjuvant treatment of locally advanced melanoma. DATA SOURCES: A literature search was performed of PubMed and the American Society of Clinical Oncology abstracts from 1976 to February 2012, using the primary search terms peginterferon alfa-2b, interferon, Sylatron, and melanoma. STUDY SELECTION AND DATA EXTRACTION: All available English-language articles and trials that described the pharmacology, pharmacokinetics, pharmacodynamics, clinical activity, or safety profile of pegIFN were reviewed. DATA SYNTHESIS: PegIFN was approved in March 2011 for the adjuvant treatment of node-positive melanoma. Interferon (IFN) is commonly used in patients with melanoma who remain at high risk for relapse following surgery; however, the optimal scheduling and dose are not agreed upon. Pegylation of IFN involves conjugation with polyethylene glycol. Following subcutaneous injection of pegIFN, the rate of absorption, renal and cellular clearance, and immunogenicity are reduced. As a result of the extended serum half-life, once-weekly administration is feasible, compared with the daily and/or thrice weekly dosing of IFN. When compared with observation alone in patients with resected stage III melanoma, pegIFN demonstrated a significant increase in relapse-free survival, with a marginal impact on overall survival. The most common adverse events were as expected with IFN and included fatigue, increased liver enzymes, pyrexia, headache, anorexia, myalgia, nausea, chills, depression, and injection site reactions. A large Phase 3 study is underway to further assess outcome and toxicity differences between pegIFN weekly and low-dose IFN thrice weekly. CONCLUSIONS: PegIFN is a modified version of the previously approved interferon indicated for the adjuvant treatment of melanoma. Although the safety profile remains similar between the pegylated and non-pegylated forms, once-weekly administration is feasible secondary to an extended serum half-life and may have improved convenience for the patient.