Purpose Studies were conducted to test whether fever-range whole body hyperthermia, rationally combined with oxaliplatin chemotherapy, would boost its efficacy without substantial toxicity. Materials and Methods The effect of heat on oxaliplatin cytotoxicity, cellular uptake, and platinum-DNA adduct formation was studied in vitro using the MTLn3 tumor cell line. In vivo, oxaliplatin was given with thermal therapy to rats bearing highly treatment-resistant MTLn3 mammary adenocarcinomas at various doses and times before, during, and after heating. Tumor growth, survival, and toxicity were measured to determine treatment outcome. Results Heating for 6h at 40°C halved the oxaliplatin IC-50 dose for MTLn3 cells. Cellular uptake of platinum and platinum adducts increased by 34% and 36%, respectively, with heat. In vivo, 50% of all rats given 10 mg/kg oxaliplatin 24h before 6h of fever-range thermal therapy were completely, immunologically, cured while a further 11% regressed their primary tumor but ultimately succumbed to metastases, and 17% experienced a limited response with increased survival. The curative response occurred only in a narrow range of doses, with most cures at 10 mg/kg. Thermochemotherapy-treated, but uncured, animals had delayed incidence and slowed growth of metastases. Anti-tumor efficacy was greatest, and toxicity was least, when oxaliplatin was administered 12 or 24 hours before FR-WB-TT. Conclusions When properly dosed and scheduled, oxaliplatin thermochemotherapy achieved permanent eradication of all primary and metastatic tumors in 50% of animals, seemingly through an immune response. Successful clinical translation of this protocol would yield hitherto unseen cures and substantial improvement in quality of life.