BACKGROUND.: This study aimed to test the safety of using perioperative high-dose-rate brachytherapy (PHDRB) in resected head and neck cancer. METHODS.: From 2000 to 2008, 97 patients received PHDRB after complete macroscopic resection. Group 1 (previously irradiated patients) received 32 to 40 Gray (Gy) of PHDRB in 8 to 10 twice-daily (bid) treatments (R0–R1 resections). Group 2 (unirradiated patients) received 16 to 24 Gy of PHDRB in 4 to 6 bid treatments (R0–R1 resections) followed by external beam irradiation (EBRT) of 45 Gy/25 daily fractions ± concomitant chemotherapy. RESULTS.: The median follow-up was 4.3 years. The cumulative hazard of 2-year grade ≥ 3 complications in group 1 was 45.9%, and the rate of grade ≥ 3 complications in group 2 was 24.6%. Actuarial locoregional control at 2 and 5 years for group 1 was 60.9% and for group 2, 84.1% and 79.4%. CONCLUSIONS.: Complications and locoregional failure rates were similar to those reported in the reference standards despite a much smaller treatment volume. © 2012 Wiley Periodicals, Inc. Head Neck, 2012