To compare preoperative chlorhexidine-alcohol topical antiseptic agent with povidone-iodine in patients undergoing abdominal hysterectomy for benign indications. A retrospective cohort study of patients undergoing abdominal hysterectomy from July 2012 to February 2015 in the Michigan Surgical Quality Collaborative was performed. The primary exposure was the use of chlorhexidine-alcohol or povidone-iodine. The primary outcome was surgical site infection within 30 days. Multivariable logistic regression and propensity score matching analysis were done to estimate the independent association of skin antiseptic choice on the rate of surgical site infection. Of the total 4,259 abdominal hysterectomies included, chlorhexidine-alcohol was used in 70.5% (n=3,005) and povidone-iodine in 29.5% (n=1,254) of surgeries. The overall unadjusted rate of any surgical site infection was 2.9% (95% CI 2.5-3.5; n=124). The unadjusted rate of surgical site infection 2.6% (95% CI 2.1-3.3; n=79) for chlorhexidine-alcohol and 3.6% (95% CI 2.7-4.8; n=45; P=.09) for the povidone-iodine group. Using multivariate logistic regression and adjusting for differences between populations in patient demographic factors (age and body mass index), medical comorbidities (American Society of Anesthesiologists class and diabetes status), perioperative variables (estimated blood loss, surgical time, intraoperative adhesions, and antibiotic categories), and hospital characteristics (bed size and teaching status), we estimate that patients receiving chlorhexidine-alcohol had 44% lower odds of developing a surgical site infection (adjusted odds ratio 0.56, 95% CI 0.37-0.85, P=.01). Propensity score matching (one to one) yielded 808 patients in the chlorhexidine-alcohol group and 845 patients in the povidone-iodine group. In the matched groups, the rate of surgical site infection was 1.5% (95% CI 0.8-2.6; n=12) for the chlorhexidine-alcohol group and 4.7% (95% CI 3.5-6.4; n=40) for the povidone-iodine group (P<.001). In abdominal hysterectomy performed for benign indications, chlorhexidine-alcohol-based skin antisepsis is associated with overall lower odds of surgical site infection compared with povidone-iodine.