Interferon-alpha-2b (INF-alpha-2b) has been approved by the FDA as adjuvant treatment for patients with melanoma at high risk of recurrence. INF-alpha-2b is administered at 20 MU/m2/day IV, 5 days per week for 4 weeks, and then 10 MU/m2/day SC, three times weekly for 48 weeks. We investigated the toxicity of this protocol in 30 patients between June 1996 and February 1998. An intensive toxicity evaluation program was developed to monitor side effects. During both induction and maintenance phases, 60% of patients required a dose delay and/or reduction. Twenty percent were unable to complete the treatment plan, and 53% tolerated at least 80% of the scheduled dose. The frequently reported toxicity during induction included constitutional symptoms, myelosuppression, and hepatotoxicity. All were reversible on cessation of treatment or dose modification. During maintenance, toxicity included thyroid dysfunction, hypertriglyceridemia, retinopathy and a combination of mood disturbances, memory loss, cognitive slowing and impaired executive function. Administration of high-dose INF-alpha-2b is feasible, with close patient monitoring.