BACKGROUNDIn this report, the authors present the results from a study of patients with unresectable oropharyngeal squamous cell carcinomas who were treated on a protocol of hyperfractionated radiation and high‐dose intraarterial cisplatin (HYPERRADPLAT) at the University of Kentucky.METHODSThe study was designed as a prospective, single‐armed case series that was conducted in the setting of a single, academic, tertiary referral center. The patient cohort consisted of 24 previously untreated patients who were diagnosed with unresectable oropharyngeal carcinoma and were treated on the HYPERRADPLAT regimen, which included hyperfractionated external beam radiotherapy (1.2 grays [Gy] twice daily) was given for 5 weeks (60 Gy) followed by high‐dose intraarterial cisplatin (150 mg/m2) and sodium thiosulfate. Shrinking “large‐field” portals were started on Week 6 and finished on Week 7 with a cumulative dose of 76.8–81.6 Gy. The main outcome measures of the study were the primary and neck response rates, the 2‐year and 5‐year overall survival and disease‐specific survival rates, and acute and late treatment morbidity.RESULTSThe median follow‐up was 77 months. Complete response rates at the primary and regional lymph nodes were both 88%. The 2‐year overall survival and disease‐specific survival rates were 57% and 68%, respectively; whereas the 5‐year overall survival and disease‐specific survival rates were 33% and 42%, respectively. Two patients had Grade 4 mucosal toxicity, and no patient experienced neurologic or significant hematologic toxicities. Within 1 year of treatment, 58% of patients had used a feeding tube.CONCLUSIONSThe HYPERRADPLAT regimen produced excellent response rates and overall survival rates comparable to those achieved by patients who had unresectable oropharyngeal carcinomas. Tolerance of the therapy was good, and further studies using HYPERRADPLAT with induction therapy may improve outcomes further in this subset of patients with unfavorable disease. Cancer 2005. © 2005 American Cancer Society.