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Interferon-α2b (IFNα2b) is the only form of systemic adjuvant therapy for stage III melanoma with documented survival benefit. Radiotherapy can also be utilized in the adjuvant setting in patients at high risk of nodal basin recurrence. As IFNα2b is associated with substantial toxicity, we sought to determine both the systemic and radiation-related toxicities in patients treated with combined adjuvant IFNα2b and regional adjuvant radiotherapy delivered in the setting of a single institution. Eighteen consecutive patients who commenced adjuvant IFNα2b between November 1997 and August 2002 were analysed retrospectively for toxicities associated with the combination of IFNα2b and adjuvant radiotherapy (40–50 Gy in 15–25 fractions) to nodal basins delivered during the maintenance phase of IFNα2b therapy (median dose during radiotherapy of 6.5 MU/m2 three times per week). Seven out of 18 patients who received concurrent radiotherapy and IFNα2b displayed grade 3 skin reactions. Severe radiation-induced toxicity was seen in three further patients, one who developed radiation pneumonitis, one who developed severe oral mucositis, and one who developed wound dehiscence that took 10 months to resolve. Non-radiation-related toxicity to IFNα2b therapy was typical for this dose and schedule. We conclude that concurrent use of adjuvant radiotherapy and IFNα2b may enhance radiation-induced toxicity. However, overall we found concurrent radiation and IFNα2b could be safely delivered with appropriate clinical monitoring.