Interferon-alpha is a pleiotropic cytokine that has been extensively evaluated in the adjuvant setting for patients with Stage II-III melanoma in spite of a lack of efficacy or proof that interferon-alpha treatment improves survival in Stage IV melanoma. Here, 12 prospective controlled Phase III trials are discussed. Adjuvant therapy with interferon-alpha has a consistent effect on disease-free survival in the overall trial experience in melanoma patients with an intermediate (Stage II) or high risk (Stage IIB-III) for relapse of malignant melanoma. Only one trial (E1684) has demonstrated a significant impact on survival but this benefit was found to be only transient at further follow-up and furthermore, was not confirmed by the subsequent E1690 trial, nor was the survival benefit confirmed by a recently published systematic review of the adjuvant trials. In the absence of a clear indication that interferon-alpha therapy has an impact on survival, whereas important toxicity is associated with tumor necrosis factor-based treatment, interferon-alpha adjuvant therapy cannot be considered standard treatment. It is too early for definitive analysis of the three largest trials and thus the mature results of these trials must be awaited. Since the impact of dose and duration of treatment also awaits further evaluation. It is reasonable to state that the role of interferon in melanoma still remains to be defined.