There is evidence that solid tumors rapidly acquire cellular resistance to cisplatin. This resistance is usually mild to moderate and could be circumvented with higher concentrations of drug exposure if ancillary methods were available to avoid systemic cytotoxicity. The purpose of this study was to determine whether a tenfold increase in dose (decadose) would overcome cisplatin resistance. In a clinical trial, response effects of cisplatin at dose intensities ranging from 32.5 to 200 mg/m2 per week, which were delivered by highly selective intra-arterial infusions with a simultaneously administered intravenous neutralizing agent, were measured in 31 patients with squamous cell carcinoma (SCC) of the upper aerodigestive tract (UADT). The overall response rate (complete response [CR] and partial response [PR] to cisplatin therapy at dose intensity intervals of 0 to 74, 75 to 149, and 150 to 200 mg/m2 per week were 45.5%, 72.7%, and 100%, respectively. The average received dose intensities for nonresponders and responders (CR and PR) were 57.8 and 120.7 mg/m2 per week, respectively (P = .031). The results indicate that resistance to standard doses of cisplatin by SCC of the UADT, both previously untreated and recurrent, can be substantially overcome with "decadose" cisplatin therapy. Progress toward improving survival of patients with head and neck cancer, and possibly other site-specific malignancies, may be achieved by incorporating decadose cisplatin therapy into a multimodality treatment plan.