Background: Twenty-four hours of perioperative antibiotics provides effective prophylaxis for most head and neck cancer resections. Many reconstructive surgeons have been hesitant to apply this standard to free-flap reconstruction of the head and neck. This prospective clinical trial compared short-course and long-course clindamycin prophylaxis for wound infection in patients with head and neck cancer undergoing free-flap reconstruction. Methods: Seventy-four patients were randomized to receive short-course (3 doses) or long-course (15 doses) clindamycin perioperatively. Wound infections, fistulas, and other postoperative complications were documented by faculty surgeons who were blinded as to treatment group. Results: The differences in wound infections and other complications were statistically insignificant. No other independent predictors of wound complications emerged in this series of patients. Conclusions: Short-course clindamycin is as effective as long-course clindamycin in preventing wound infections after free-flap surgery for head and neck ablative defects.