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Notes: Background  A multicentre, centrally randomized, open-labelled study with temozolomide and interferon (IFN)-α2b was carried out to study the therapeutic effect in patients with metastatic melanoma stage IV.Objectives  The response rate, efficacy, side-effects, reasons for discontinuation of therapy and survival rate of 47 patients treated with temozolomide in combination with two different dosing regimens of IFN-α2b were documented.Patients/methods  Twenty-nine male and 18 female patients (mean age 57·6 years, range 34–74) were centrally randomized to two different arms: 20 patients received a treatment schedule with temozolomide 150 mg m−2 on days 1–5 orally every 28 days in combination with IFN-α2b 10 MIU m−2 every other day and 27 patients received temozolomide 150 mg m−2 on days 1–5 every 28 days in combination with IFN-α2b in a fixed dose of 10 MIU every other day.Results  We observed an overall response rate of 27·6% comprising five complete remissions (10·6%: one patient group A, four patients group B), in two of these five patients at the last follow-up in the study (4·3%, both in group B); and eight partial remissions (17%: six patients in group A, two patients in group B), in three of these eight patients at the last follow-up in the study (6·4%, two patients in group A, one patient in group B). Three patients showed stable disease (6·4%: one patient in group A, two patients in group B). Mean survival was 14·5 months [95% confidence interval (CI) 10–19] with no significant differences between treatment groups. However, there was a significant correlation with response after three cycles (log rank test, P 〈 0·03). Within the 32 patients who completed at least three cycles of therapy, seven patients (three in group A and four in group B) with a partial or complete response showed a significantly better mean survival of 30·6 months (95% CI 19·1–42) compared with 25 patients who did not respond (13·7 months 95% CI 9·2–18·3). In total, patients with at least one complete remission showed the longest survival (37·1 months 95% CI 26·3–47·9), followed by patients with at least one partial response (17·4 95% CI 10·9–23·9). Major side-effects of the treatment were nausea, vomiting, headache, leucopenia, thrombopenia, elevation of liver function parameters and neurological symptoms. In five patients, the side-effects led to a discontinuation of treatment: neurological symptoms (two patients), sepsis (one patient), brain haemorrhage (one patient) and exanthema (one patient). There were no treatment-related deaths.Conclusions  The combination of temozolomide and IFN-α2b can easily be administered and shows tolerable toxicity. When an objective response occurs after three cycles, it indicates a significant survival advantage.