Cisplatin is one of the most active chemotherapeutic agents for the treatment of squamous carcinoma of the head and neck; however, neurotoxicity and nephrotoxicity are dose-limiting. The analog, carboplatin, is a promising new agent with similar activity but a different spectrum of toxicity. To evaluate if a therapeutic advantage could be achieved with acceptable toxicity, a combination of carboplatin 350 mg/m2 and cisplatin 50 mg/m2 were administered every 28 days to patients with recurrent or metastatic disease who had received no prior chemotherapy. Of 24 patients enrolled in this study, 21 were assessable for response and toxicity. Five partial responses were observed (24%; 95% confidence interval [Cl], 4.9% to 38.6%). No complete response occurred. Two of these patients received definitive radiotherapy and achieved complete responses. The median survival of all patients was 24 weeks. Hematologic toxicity was dose-limiting necessitating a decrease in the starting dose of carboplatin to 300 mg/m2. Nonhematologic toxicity was infrequent and mild. Significant renal impairment occurred in only two patients. Although treatment with the combination of carboplatin and cisplatin is feasible, we found no therapeutic advantage in terms of an increased response or survival.