Recombinant interferon-alfa (Intron A, Roferon-A) has been under investigation as a therapeutic agent for non-Hodgkin's lymphoma (NHL) for 25 years. It has antitumor efficacy in a number of histologic subtypes but has not been accepted as a clinically useful agent by the majority of oncologists/hematologists. A total of 10 prospective, randomized trials of interferon-alfa have been conducted in patients with follicular lymphoma. A survival benefit associated with interferon-alfa has been demonstrated in three of these trials, which used an anthracycline-based combination chemotherapy induction regimen, primarily in patients with bulky symptomatic disease. In this article, we review these trials, as well as the use of interferon-alfa in other NHL subtypes. Based on these data, we support the recommendation that interferon-alfa be added to an anthracycline-based induction regimen in the treatment of patients with clinically or histologically aggressive follicular lymphoma. This agent also appears to be effective in patients with diffuse large B-cell lymphoma and in patients with cutaneous T-cell lymphoma. Preliminary clinical data support the need for prospective, randomized phase III trials evaluating the role of interferon-alfa in these disorders.