Interferon alpha2b has recently been shown to improve outcome in patients with metastatic malignant melanoma. The high-dose interferon therapy used is however associated with significant systemic adverse effects. These adverse effects are likely related to the multitude of actions of interferon which in addition to its antineoplastic effects also possesses antiviral and immunomodulating properties. Elucidation of the mechanism of the antiproliferative effects of interferon may allow for the development of agents that possess the antineoplastic properties while being devoid of the other effects that make interferon toxic. In the animal model developed for this study tumors in mice receiving interferon alpha2b grew at a slower rate and achieved a small final tumor volume (3040 +/- 690 vs 1400 +/- 314 mm3 for the control and treated groups respectively, P < 0.05). Furthermore the final tumor weight in the treated group was significantly smaller (1.50 +/- 0.21 g vs 2.76 +/- 0.46 g for the treated and control groups respectively; P = 0.036). The (3-[4,5-Dimethylthiazol-2-y]-2,5-diphenyltetrazolium bromide) (MTT) colorimetric assay failed to reveal any direct effects of interferon alpha2b on this murine melanoma cell line. This antiproliferative effect of interferon alpha2b was in addition found to be independent of alterations in the expression of the angiogenic cytokines vascular endothelial growth factor, basic fibroblast growth factor, and transforming growth factor beta.