From August 1979 to June 1983, the RTOG conducted a prospective Phase III study that compared a standard schedule with five fractions per week of 180 to 200 cGy per day to a total dose of 6600-7380 cGy, with a hyperfractionation regimen consisting of two fractions of 120 cGy per day, separated by a rest period of 3 to 6 hours for a total of 6000 cGy. A total of 210 patients were entered, of which 187 are analyzed. Complete initial tumor clearance in the head and neck was achieved by radiotherapy in 61% of the patients assigned to the standard schedules and in 59% of those assigned to the continuous hyperfractionation schedule; surgical salvage contributed towards achieving complete response in 5% and 7% of patients, respectively. The Kaplan-Meier estimates for loco-regional control of tumor at 1 and 2 years was 39% and 29% for the standard schedules, and 43% and 30% for the hyperfractionation schedule. The endpoints examined to evaluate therapeutic effects do not indicate that the stated hyperfractionation schedule is different than the standard RTOG treatment schedule for head and neck cancer. Acute normal tissue reactions appear to be more severe with the hyperfractionation schedule but the incidence of late reactions is similar in both groups. There is a tendency toward more severe acute reactions when the interval between the two fractions per day is 4.5 hrs or less in comparison to intervals longer than 4.5 hrs.