Background: In October 2013, the University of Maryland Medical Center established a formal antibiotic prophylaxis protocol for patients undergoing ventricular assist device (VAD) placement, replacing a previous system of various broad-spectrum antibiotic combinations typically for prolonged durations based on surgeon preference. This new protocol consisted of a standardized regimen of 72 hours of vancomycin and ceftriaxone after the procedure. The objective of this project was to evaluate the rate of surgical site infection (SSI) related to VAD placement to ensure that implementing the new protocol did not cause an increase in SSI rates. Methods: The study was a retrospective cohort study of patients who had undergone VAD placement before the protocol change (January 1, 2011, to October 1, 2013) and after the change (October 1, 2013, to November 15, 2015). The primary outcomes was the difference in SSI rate before and after the protocol change using CDC NHSN definitions. Pertinent data points of interest included reason for VAD placement, duration/type of antibiotics used, delayed sternal closure, SSI, characterization of infection (bloodstream, driveline, or pocket), organism identified on culture and mortality at 30 days and 1 year. SSI rates were assessed using the Fischer exact test, and descriptive statistics were used for other outcome variables. Results: In total, 75 patients were included before the protocol and 46 after the protocol change. Overall, 27% and 17% of patients were on therapeutic antibiotics prior to the VAD placement, respectively (P = 0.23). Also, 8 (6.6%) patients in the preintervention group had an SSI compared to 1 patient (0.8%) in the postintervention group (P = .15). Adherence to the protocol was suboptimal, with 27% of patients in the postintervention group receiving non–protocol-adherent antibiotics and 65% of patients receiving antibiotics >96 hours postoperatively. When evaluating the patients collectively, SSI rates were the same when antibiotics were discontinued <72 hours postoperatively versus when antibiotics were continued beyond 72 hours postoperatively or were not given at all postoperatively (3.1% vs 10.7% vs 0%; P = .24). SSI rates were also no different among patients who received cefazolin monotherapy (0%), vancomycin and ceftriaxone (2.7%), vancomycin and piperacillin tazobactam (2%), and other antibiotic combinations (7.7%) for surgical prophylaxis (P = 0.1). Conclusions: No change in SSI rates was noted after a protocol change narrowing the spectrum and duration of antibiotic prophylaxis was implemented. Evaluation of optimal surgical prophylaxis in this patient population is difficult due to low event rates and frequent therapeutic indications for antibiotics outside the standard prophylaxis. Despite these challenges, this study supports the safety of studying SSI prophylaxis reduction in the VAD population. Further studies are reasonable and warranted.