Interferon treatment has been shown to cause myelosuppression in man and in a mouse model. Combinations of interferon-gamma (IFN-gamma) with either interferon-alpha (IFN-alpha) or interferon-beta (IFN-beta) cause the synergistic enhancement of interferons' antiviral, antiproliferative, antitumor, and immunoregulatory activities. Thus, combinations of MuIFN-beta and either natural or recombinant DNA-derived MuIFN-gamma were evaluated for their ability to cause the synergistic enhancement of interferon's myelosuppressive activity. The combinations of interferons were evaluated in vitro in bone-marrow colony-stimulating assays. They were seen to potentiate the in vitro myelosuppressive effect of the interferons. The combinations were evaluated for their in vivo myelosuppressive effect in mice. Treatment with the separate interferons caused a significant reduction in the number of circulating leukocytes, suggesting a potent myelosuppressive effect. However, treatment with the interferons in combination caused an antagonism and led to a myelosuppressive effect which was no greater than that of the interferons alone. The combinations of interferons were employed at concentrations which have been shown to provide substantial potentiation of the antitumor action of the interferons against B-16 melanoma. Thus, the data suggest that combination interferon therapy employing IFN-gamma together with either IFN-alpha or IFN-beta provide a potentiated antitumor activity without increasing the myelosuppressive side effect of the therapy.