Purpose To test whether altered radiation fractionation schemes (hyperfractionation [HFX], accelerated fractionation, continuous [AFX-C], and accelerated fractionation with split [AFX-S]) improved local-regional control (LRC) rates for patients with squamous cell cancers (SCC) of the head and neck when compared with standard fractionation (SFX) of 70 Gy. Methods and Materials Patients with stage III or IV (or stage II base of tongue) SCC (n=1076) were randomized to 4 treatment arms: (1) SFX, 70 Gy/35 daily fractions/7 weeks; (2) HFX, 81.6 Gy/68 twice-daily fractions/7 weeks; (3) AFX-S, 67.2 Gy/42 fractions/6 weeks with a 2-week rest after 38.4 Gy; and (4) AFX-C, 72 Gy/42 fractions/6 weeks. The 3 experimental arms were to be compared with SFX. Results With patients censored for LRC at 5 years, only the comparison of HFX with SFX was significantly different: HFX, hazard ratio (HR) 0.79 (95% confidence interval 0.62-1.00), P=.05; AFX-C, 0.82 (95% confidence interval 0.65-1.05), P=.11. With patients censored at 5 years, HFX improved overall survival (HR 0.81, P=.05). Prevalence of any grade 3, 4, or 5 toxicity at 5 years; any feeding tube use after 180 days; or feeding tube use at 1 year did not differ significantly when the experimental arms were compared with SFX. When 7-week treatments were compared with 6-week treatments, accelerated fractionation appeared to increase grade 3, 4 or 5 toxicity at 5 years (P=.06). When the worst toxicity per patient was considered by treatment only, the AFX-C arm seemed to trend worse than the SFX arm when grade 0-2 was compared with grade 3-5 toxicity (P=.09). Conclusions At 5 years, only HFX improved LRC and overall survival for patients with locally advanced SCC without increasing late toxicity. © 2014 Elsevier Inc. All rights reserved.