Forty-eight patients with locally confined (M0) squamous cell head and neck cancer were prospectively randomized to receive either simultaneous (SIM) or sequential (SEQ) combined technique therapy with a 5-fluorouracil infusion, a cisplatin bolus injection, and radiation therapy. Patients with residual resectable disease underwent surgery after induction therapy, whereas those achieving a complete response to induction did not require surgery. Patients on the two treatment arms were equivalent in all measured variables, including disease extent. Toxicities of the SIM and SEQ arms also were equivalent except for mucositis and the resultant weight loss, which were more severe on the SIM arm (P = 0.002). With a follow-up time ranging from 9 to 41 months, seven of the 24 SIM patients and 14 of the 24 SEQ patients are considered treatment failures. The relapse-free survival is significantly better on the SIM arm (P = 0.03), although an overall survival advantage has not yet been demonstrated (P = 0.13). The achievement of a complete response after induction therapy correlates with both the relapse-free (P = 0.0005) and overall (P = 0.05) survival, and the likelihood of an induction complete response also is significantly better for those treated with the SIM schedule (P = 0.02). Eighteen patients did not require surgery after achieving an induction complete response. Relapse-free survival does not appear to be compromised in this patient subset.