Although adjuvant high-dose interferon α-2b therapy significantly improves recurrence-free survival vs. observation in high-risk resected melanoma, the overall survival benefit is presently unclear. Pegylation of interferon α-2b (peginterferon α-2b) allows for a reduction in the dosing frequency with increased drug exposure. Adjuvant peginterferon α-2b therapy has also been shown to provide a significant, sustained improvement in recurrence-free survival compared with observation in patients with stage III melanoma. We report on the use of adjuvant peginterferon α-2b (3 μg/kg/week) in clinical practice in a series of 8 patients treated at the Universitätsklinikum Essen in Germany following complete resection of primary melanoma at intermediate- and high-risk of recurrence (stage II-III). Treatment duration ranged from 2 to 29 months, with 4 patients receiving long-term therapy (≥24 months). Following treatment, 5 patients (stage II) remained disease-free at 33, 33, 37, 39 and 43 months from the time of diagnosis. In 2 patients, peginterferon α-2b was terminated 4 and 9 months after treatment initiation due to disease progression. Once-weekly subcutaneous administration of peginterferon α-2b was convenient in all patients. In 3 patients experiencing adverse events, dose reductions led to a resolution of symptoms and enabled treatment to continue long-term. Three further patients discontinued therapy due to adverse events at 2, 8 and 27 months of therapy (persistent elevation of γ-glutamyl transpeptidase, liver transaminase elevation and urosepsis); dose modifications were not applicable in these patients. Thus, long-term adjuvant peginterferon α-2b therapy was feasible in the clinical practice setting and was generally well tolerated in these intermediate- and high-risk melanoma patients.