BACKGROUND: The role of interferon (IFN) in the treatment of multiple myeloma has been investigated for nearly two decades. The mechanisms underlying antitumor activity of IFN may be mediated by antiproliferative and immunomodulatory effects. The benefits of treatment remain controversial, and guidelines for the use of IFN in myeloma are needed. This review evaluates available data on the impact of IFN therapy on multiple myeloma. METHODS: A MEDLINE search of published prospective, randomized trials of IFN in multiple myeloma provided the data included in this review, as well as selected abstracts presented at international meetings. RESULTS: IFN has complex and pleiotropic effects on human myeloma lines and ex vivo myeloma cells. An antiproliferative effect with disruption of the IL-6-mediated growth loop may be crucial, but biologic heterogeneity in myeloma may have important clinical implications for response to IFN. IFN has demonstrable antitumor activity in multiple myeloma but appears to have a modest effect on overall survival when combined with chemotherapy during induction or when used as maintenance therapy. Most studies have shown a prolongation of the plateau phase of disease with IFN of variable duration of between four and 12 months. CONCLUSIONS: A reliable estimate of the benefit of IFN in the overall population of patients with myeloma is difficult to determine with discordant results from different trials. Possible sources of heterogeneity in randomized trials need to be identified, and recognition of subsets of patients who may benefit is important. Cost-benefit analyses with integration of quality-of-life data are essential for developing guidelines for the use of IFN in myeloma.