High-dose interferon-alpha2b is a U.S. Food and Drug Administration-approved adjuvant treatment for stage III melanoma, and yet, because of its limited efficacy and well-known toxicity, it is not universally accepted by patients and oncologists. In this paper, we evaluate the benefits and risks of adjuvant high-dose interferon-alpha2b and try to provide a framework to help oncologists guide patients trying to decide whether to undergo adjuvant high-dose interferon therapy.