The aim of this prospective study was to record the pattern of failure associated with high-dose interferon-alpha2b (IFN) adjuvant therapy after surgery. It included 55 consecutive patients with stage IIB and III melanoma (median age 50 years) rendered disease-free by surgery but considered at high risk for relapse from a tertiary referral, university-affiliated medical centre. Intervention consisted of IFN 20 mU/m(2) per day intravenously, 5 days a week for 4 weeks, followed by subcutaneous IFN 10 mU/m(2) per day three times a week for 48 weeks. Treatment was stopped at completion of protocol, at disease progression or due to unacceptable toxicity. Dose modification followed treatment-related toxicity. Twenty-six of the 55 patients (47%) relapsed: 14 during treatment and 12 after completion of the protocol. Eighteen of these 26 patients (69%) relapsed initially in a single organ, most commonly in soft tissue or the CNS. A single metastasis was noted in 12 of the 18 patients, and multiple metastases confined to a single organ were detected in the other six. No statistically significant survival advantage could be demonstrated in association with any of the patterns of relapse. Patients treated for stage IIB disease fared better than those treated for stage III disease, regardless of whether the regional metastases were microscopic or palpable. IFN seems to be more commonly associated with a single-organ/single-metastasis pattern of failure, and more soft tissue and CNS relapses. This pattern did not translate into a survival advantage in this series. Larger databases should be explored to validate these trends.