We have examined the ability of misonidazole (MISO) or etanidazole (ETA) to improve the antitumor efficacy of cisplatin (CDDP), hyperthermia, and radiation in the FSaIIC murine fibrosarcoma. A growth delay of about 25 days was produced with CDDP (5 mg/kg) and hyperthermia (43 degrees C, 30 min) prior to radiation (3 Gy daily for 5 days) on day 1. The addition of MISO (1 g/kg) on day 1 resulted in a tumor growth delay of about 28 days. The addition of ETA at 0.5 g/kg or 1 g/kg resulted in tumor growth delays of about 33 and 43 days, respectively. Tumor cell survival assay showed that MISO was additive with CDDP either at 37 degrees C or with hyperthermia (43 degrees C, 30 min). In contrast, ETA at both 0.5 g/kg and 1 g/kg was dose modifying over the CDDP dosage range at 37 degrees C or 43 degrees C. Analysis of tumor cell killing in Hoechst 33342 selected bright (presumably oxic) and dim (presumably hypoxic) tumor cell subpopulations demonstrated that the addition of MISO to the CDDP trimodality regimen increased killing in the dim cell subpopulation, while the addition of ETA increased tumor cell killing in both subpopulations, although the greater effect was in the dim cell subpopulation. These results indicate that ETA may add to the efficacy of the CDDP trimodality in the clinic and may be of value as a chemosensitizer with CDDP.