Melanoma cells are resistant to radiation in part due to their capacity to repair sublethal damage. A large fraction dose is therefore often utilized. However, if the tumour is located close to critical structures with modest tolerance, high fraction doses increase the risk for late complications compared with standard fractionation, but using the latter alone risks the desired outcome. Concurrent systemic biotherapy with standard radiation fractions may therefore represent an acceptable compromise. The outcome of concurrent systemic interferon-alpha (IFNalpha) and radiation in three patients with head and neck melanoma was evaluated. Standard radiation fractions were used because of the radiosensitizing properties of IFNalpha. Acute toxicity was significant and required treatment interruptions. However, all side effects subsided following treatment. All three patients achieved local control at follow-up periods of 24, 18 and 19 months, respectively. One patient developed widespread distant metastases. The combination of IFNalpha with radiation is considered feasible in terms of outcome and should be investigated with a larger cohort of patients. Toxicity is significant, and the addition of radioprotectors could be desirable.