OBJECTIVE The goal of this long-term quasi-experimental retrospective study was to assess the impact of a 5-year serial infection control and antimicrobial stewardship intervention on surgical site infections (SSIs). METHODS This study was conducted in a tertiary-care public teaching institution over a 5-year period from January 2010 to December 2014. All patients undergoing hepatobiliary surgery and liver, kidney, pancreas, and simultaneous pancreas-kidney transplantation were included. Outcomes were compared between a preintervention group (2010-2011) and a postintervention group (2012-2014). RESULTS A total of 1,424 procedures averaged an overall SSI rate of 11.2%. After implementation of the interventions, a decrease of 52.8% in SSI rates from 17.4% to 8.2% was observed (P50% (relative rate; P<.001) was observed in superficial incisional and organ-space infections between pre- and postintervention groups. In addition, a 54.9% decrease from 19.7% to 8.9% (P<.001; OR, 2.2; 95% CI, 1.4-3.5) and a 51.6% decrease from 15.5% to 7.5% (P=.001; OR, 2.2; 95% CI, 1.4-3.5) were observed for SSI rates in hepatobiliary surgery and solid organ transplantation, respectively. The antimicrobial stewardship intervention increased overall conformity to the internal surgical prophylaxis protocol by 15.2% (absolute rate) from 45.1% to 60.3% (P<.003; 95% CI, 5.4-24.9). CONCLUSIONS A long-term serial infection control and antimicrobial stewardship intervention decreased SSIs among patients undergoing hepatobiliary surgery and liver, kidney, pancreas, and simultaneous pancreas-kidney transplantation. Infect Control Hosp Epidemiol 2016;1468-1474.