The optimal fractionation schedule for radiotherapy of head and neck cancer has been controversial. The objective of this randomized trial was to test the efficacy of hyperfractionation vs. standard fractionation. Patients with squamous cell carcinoma of head and neck organs were randomly assigned to receive radiotherapy delivered with A) standard fractionation at 2 Gy/fraction/day, 5 days/week, to 65-70 Gy/7 weeks; B) hyperfractionation at 1.2 Gy/fraction, twice daily, 5 days/week to 75 80 Gy/7 weeks. All patients but one completed the treatment. The median follow-up was 24 months for all patients. Patients treated with hyperfractionation had significantly better local-regional control (p<0.005) than those treated with standard fractionation. Although acute morbidity was somewhat higher in the hyperfractionated radiotherapy group, late disturbing effect was much lower in this group. In conclusion, hyperfractionation is more efficacious than standard fractionation for locally advanced head and neck cancer. Acute but not late effects are also increased. MJIRI, Vol. 18, No.3, 231-235, 2004.