Background: Prior studies suggest that cefazolin, widely used for antibiotic prophylaxis in hysterectomy, might not prevent surgical site infections (SSIs) as well as antibiotics with a broader antianaerobic antimicrobial spectrum. We compared the effectiveness of cefazolin versus antibiotic regimens with a broader antimicrobial spectrum in a ≥500-bed regional referral center. Methods: Study design: retrospective cohort. Population and setting: patients ≥18 years old who underwent hysterectomy between 1998 and 2018 at the University of Wisconsin Hospital. Analysis: propensity score matching with a caliper of 0.2 to select controls for cefazolin treatment, matching on: age, body mass index (BMI), diabetes, length of stay, duration of surgery, and preoperative renal function. We conducted a crude SSI incidence analysis and adjusted for additional covariates (malignancy, intraoperative temperature, and preoperative glucose level) using a Cox proportional hazards model. All analyses were conducted using STATA SE v15 software. Results: We had 4,087 hysterectomy patients, with 123 SSIs (3%). Among these SSIs, 46%, 11%, and 42% were superficial, deep, and organ-space, respectively. Malignancies were present in 83% of SSI patients, with 30% being ovarian cancer. Risk factors for SSI in the unmatched sample multivariable analysis (MV) were length of stay (aHR, 1.1; 95% CI, 1.05–1.1; P < .001), duration of surgery (aHR, 1.2; 95% CI, 1.1–1.32; P < .001), and BMI (aHR, 1.04; 95% CI, 1.02–1.06; P < .001). After propensity matching, 2,282 hysterectomies remained. In the crude incidence analysis, cefazolin (IR, 6.0) had a protective SSI effect compared to cefoxitin (IR, 7.1), ciprofloxacin/metronidazole (IR, 27.2), clindamycin/gentamicin (IR, 14.1), any antianaerobic regimen (IR, 8.0), and regimens not guideline recommended (IR, 11.7). In our MV analyses of cefazolin versus comparator antibiotic regimens, we found that hypothermia was consistently associated with a higher SSI risk (P ≤ .03). Receipt of a β-lactam antibiotic regimen was associated with a significantly lower SSI risk (aHR, 0.31; 95% CI, 0.11–0.89, P = .03), but cefazolin’s protective SSI effect was no longer statistically significant. Conclusions: We found that cefazolin had a lower SSI risk compared to other antibiotic regimens, including those with better antianaerobic spectrum, in our tertiary-care hospital’s 11-year high-risk cohort. Our analysis suggests that maintaining intraoperative normothermia and administering β-lactam antibiotic prophylaxis are important modifiable risk factors for SSI prevention.