Interferon (IFN) is the most studied and the only approved adjuvant therapy for melanoma. There are 2 formulations of IFN, conventional IFN and pegylated IFN (peg-IFN), which have been investigated in multiple randomized clinical trials. We have compared the feasibility and tolerability of low-dose conventional IFN and peg-IFN in real life, outside the controlled settings of clinical trials. In this study, we analyzed 99 patients with resected melanoma, who were treated with either conventional IFN (n=48) or with peg-IFN (n=51), retrospectively. The median treatment duration in conventional IFN group was 13.3 versus 16.5 months in peg-IFN (P=0.52). Moreover, patients with peg-IFN tended to have dose reduction or treatment discontinuation due to adverse events (AE) significantly more often. In addition, neutropenia occurred significantly more often in peg-IFN group versus IFN group (n=2; 5% conventional vs. n=16; 36.4% peg-IFN, P=0.00). More than 90% of these patients developed only grade 2 neutropenia and there were no reported infections. We conclude that the 100 µg flat dose peg-IFN, which is commonly referred to as "low-dose," actually represents a higher dose of IFN, which consequently results in more frequent dose reductions and discontinuation of treatment. The use of peg-IFN is certainly more convenient for the patient in terms of application, thus close monitoring, early medical interventions, and dose adjustments to avoid treatment discontinuation are crucial for compliance.