We have investigated the antiproliferative activities of recombinant rat-gamma-interferon and recombinant human tumor necrosis factor alpha in a rat renal cell carcinoma model system. The tumor was transplanted subcutaneously, the drugs were administered peritumorally. Gamma-interferon treatment starting two days after tumor implantation resulted in a dose-dependent growth inhibiting effect. Tumor necrosis factor alpha was only effective at the highest concentration. Different combinations of the drugs have additive or synergistic antiproliferative effects. The combination of both highest doses completely inhibited tumor growth without any obvious toxic effects on the rats. Rechallenge of the cured rats with a tumor piece in the contralateral flank did not result in a tumor specific immune response. Shortening of the treatment period to two weeks resulted in an increased lag-period, but finally all tumors started to grow. Furthermore, the anti-tumor effect was dependent on tumor volume at start of therapy. Monotherapy could not inhibit tumor growth of an established tumor. The combination with both highest doses, however, inhibited tumor growth even when treatment was started at a tumor volume of two to five cm3. Treatment with gamma-interferon and tumor necrosis factor is most effective at low tumor burden. These studies suggest that clinical application of these drugs is most effective in an adjuvant setting.