Major prognostic factors for melanoma include thickness of the primary lesion, ulceration and presence or absence of regional lymph node metastases. These parameters form the basis for the American Joint Committee on Cancer staging system and the determination of the appropriateness of post-surgical adjuvant therapy. Among the numerous agents tested for the adjuvant therapy of high-risk melanoma, interferon-alpha 2b (IFN-alpha2b) administered at maximally tolerated doses is the only one to demonstrate an improvement in relapse-free and overall survival for these patients. This high-dose IFN-alpha2b regimen comprising an intensive intravenous induction phase followed by a more prolonged subcutaneously administered phase has now been tested in three, large, randomised trials done through the United States Cooperative Groups, and has shown consistent benefit in preventing relapse and improving survival for patients with thick primary melanomas and those with regional lymph node metastases. The relative importance of the induction component of this treatment regimen is being addressed in an ongoing intergroup trial for intermediate-risk melanoma. Data from completed and ongoing studies using high-dose IFN-alpha for the adjuvant therapy of melanoma are presented.