Administration of interleukin-1 alpha (IL-1 alpha) plus certain cytotoxic drugs causes substantially greater clonogenic tumor-cell kill and tumor-regrowth delay than does treatment with either agent alone. IL-1 alpha itself has little effect on tumor growth despite its ability to induce acute hemorrhagic necrosis, restrict tumor blood flow, and cause microvascular injury in a variety of murine model systems. To investigate further IL-1 alpha's ability to enhance the antitumor activity of cytotoxic drugs, we initiated studies to examine the effect of IL-1 alpha on cisplatin (cDDP)-mediated cytotoxicity using the RIF-1 tumor system. The antitumor activity of IL-1 alpha and cDDP was quantitated through standard clonogenic tumor-cell survival assays, a tumor hemorrhagic necrosis assay and tumor-regrowth delay studies, with the interaction between IL-1 alpha and cDDP being analyzed through median dose-effect. In vitro, IL-1 alpha had no enhancing effect on the cDDP-mediated tumor-cell kill. For examination of the in vivo efficacy of this regimen, RIF-1 tumor-bearing C3H/HeJ mice (14 days postimplantation) were treated concurrently with single i.p. injections of IL-1 alpha and/or cDDP at various doses. The increased clonogenic tumor-cell kill obtained with IL-1 alpha/cDDP was dose-dependent, with significant enhancement by IL-1 alpha being observed (P < 0.001), even at the lowest doses tested (2 mg/kg and 6 micrograms/kg for cDDP and IL-1 alpha, respectively), but it did not correlate with an increase in tumor hemorrhage. Using median dose-effect analysis, this interaction was determined to be strongly synergistic. When treated animals were monitored for long-term antitumor effects, combinations with IL-1 alpha significantly increased the tumor-regrowth delay and decreased the fractional tumor volume (P < 0.001). These results demonstrate that IL-1 alpha synergistically enhances cDDP mediated in vivo antitumor activity and suggest that the combination of IL-1 alpha and cDDP may have potential therapeutic application in the design of effective treatment modalities for cancer.