OBJECTIVE The authors sought to determine the effects of eliminating the use of prolonged prophylactic systemic antibiotics (PPSAs) in patients with subdural and subgaleal drains. METHODS Using a retrospective database, the authors collected data for patients over the age of 17 years who had undergone cranial surgery at their institution between December 2013 and July 2014 (PPSAs period) or between December 2014 and July 2015 (non-PPSAs period) and had subdural or subgaleal drains left in place postoperatively. RESULTS One hundred five patients in the PPSAs period and 80 in the non-PPSAs period were identified. The discontinuation of PPSAs did not result in an increase in the frequency of surgical site infection (SSI). The frequency of Clostridium difficile (CDI) and the growth of resistant bacteria were reduced in the non-PPSAs period in comparison with the PPSAs period. In the 8 months after the drain prophylaxis protocol was changed, $93,194.63 were saved in the costs of antibiotics and complications related to antibiotics. CONCLUSIONS After discontinuing PPSAs for patients with subdural or subgaleal drains at their institution, the authors did not observe an increase in the frequency of SSI. They did, however, note a decrease in the frequency of CDI and the growth of resistant organisms. It appears that not only can patients in this population do without PPSAs, but also that complications are avoided when antibiotic use is limited to 24 hours after surgery.