This successor phase II study evaluates the tolerability and efficacy of concomitant hyperfractionated radiation therapy (HFX-RT) and double dose intra-arterial (IA) cisplatin in patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN). In doing so, this study represents further resurgence of the potential use of IA chemotherapy in the management of SCCHN. This has been enabled by the evolution of angiographic catheter/microcatherter technology. Between 1997 and 1999, 24 patients with locally advanced T4/T3 SCCHN were treated with HFX-RT (76.8- 81.6 Gy at 1.2 Gy bid over 6-7 weeks) and high-dose IA cisplatin (150mg/m2 given at the start of and during RT boost treatment [start of week 6 and 7]). Twenty-two patients (92%) had T4 disease and 14 (58%) N2/ N3 disease. Acute toxicity was limited to two grade 4 (8%) and 19 grade 3 (79%) mucosal events; and single grade 3 hematologic, infectious and skin events. Eight patients (33%) were unable to receive the second planned dose of IA cisplatin. Twenty-two patients had complete response (92%) at the primary site. Among 17 patients with positive neck disease 12 (71%) achieved complete response in the neck. Follow-up ranges from 7-30 months (median = 18 months) with 14 patients alive without disease, 2 alive with disease, 7 dead of disease and 1 dead of intercurrent disease. While concomitant HFX-RT and double dose IA cisplatin as used in this study is associated with encouraging response rates in this highly unfavorable subset of patients with locally advanced SCCHN it was not feasible. Future investigation of this novel treatment strategy utilizing modern angiographic catheter/microcatherter technology will involve a single dose of IA cisplatin with HFX-RT and dose intensification using neoadjuvant therapy.