Fifty-seven patients with advanced squamous carcinoma of the larynx and hypopharynx were entered on a pilot study of initial therapy using split course radiation therapy combined with simultaneous chemotherapy using mitomycin-C and 5-fluorouracil. The treatment was well tolerated with 90% of patients completing their planned radiation treatment. Seventy percent of this group completed their planned chemotherapy. Significant hematological toxicity was not observed. Survival and loco regional control at one and two years of follow-up were considered at least comparable to that achieved with conventional single-course radical radiation therapy as primary treatment. Based on these results a randomized trial of this radiation-chemotherapy regimen compared to radiation therapy alone as initial therapy is in progress.