Background: Free tissue reconstruction has become the standard of care for most major defects in the head and neck. Surgical site infection (SSI) can lead to vessel thrombosis and eventual flap loss. The use of antibiotics after free tissue reconstruction has not been studied in the current environment of heightened bacterial antibiotic resistance. We compared the use of short-term and longer-term antibiotics in a series of patients receiving free tissue reconstructions. Methods: A retrospective review was performed of 147 patients receiving 149 free flaps who were treated with either short-course (≤2 d; n = 149 [43%]) or long-course (>2 d; n = 85 [57%])) post-operative antibiotics from 2009 to 2014. The outcomes examined were infection, return to the operating room, length of hospital stay, and patient death up to six weeks post-surgery. In addition, risk factors associated with SSI were explored. Results: Surgical site infection, flap dehiscence, flap loss, and length of stay were not different in the two groups. However, those receiving long-course antibiotics had a significantly higher rate of pneumonia (24.7% vs. 10.9%; p = 0.03), although they had a lower rate of urinary tract infection (0.0% vs 9.4%, respectively; p = 0.01). Body mass index remained a statistically significant risk factor in the multivariable analysis (p = 0.005). Conclusion: Prolonged antibiotic use after free flap reconstruction of head and neck defects does not appear to prevent SSI better than short-course treatment in this population. Moreover, long-course antibiotic use was associated with a higher risk of pneumonia.