Many guidelines recommend a weight-adopted dose increase of cefuroxime for surgical antimicrobial prophylaxis (SAP). However, the evidence that this approach is associated with lower rates of surgical site infection (SSI) is limited. To assess whether double-dose cefuroxime SAP was associated with a decreased SSI rate in patients weighing at least 80 kg. This cohort study included adult patients (>18 years) weighing at least 80 kg who underwent 9 major surgical procedures with a cefuroxime SAP administration from the Swissnoso SSI surveillance system between January 2015 and December 2019 at 142 Swiss hospitals. The follow-up was 30 days for all surgical procedures and 1 year for implant-related operations. Cefuroxime SAP dose (1.5 vs 3.0 g). Overall SSI. A mixed-effects logistic regression adjusted for institutional, epidemiological, and perioperative variables was applied. Results were stratified by weight categories as well as by wound contamination classes. Of 41 076 eligible patients, 37 640 were included, with 22 625 (60.1%) men and a median (IQR) age of 61.9 (49.9-71.1) years. The outcome SSI was met by 1203 patients (3.2%). Double-dose cefuroxime was administered to 13 246 patients (35.2%) and was not significantly associated with a lower SSI rate (adjusted odds ratio aOR, 0.89; 95% CI, 0.78-1.02; P = .10). After stratification by weight category, double-dose SAP vs single-dose SAP was associated with lower SSI rates among 16 605 patients weighing at least 80 to less than 90 kg (aOR, 0.76; 95% CI, 0.61-0.97; P = .02) but not in the other weight categories (≥90 to <100 kg, 10 342 patients: aOR, 1.12; 95% CI, 0.87-1.47; P = .37; ≥100 to <120 kg, 8099 patients: aOR, 0.99; 95% CI, 0.76-1.30; P = .96; ≥120 kg, 2594 patients: aOR, 0.65; 95% CI, 0.42-1.04; P = .06). After stratification by contamination class, double-dose SAP was associated with lower SSI rates among 1946 patients with contaminated wounds (aOR, 0.49; 95% CI, 0.30-0.84; P = .008) but not those with clean wounds (25 680 patients; aOR, 0.92; 95% CI, 0.76-1.12; P = .44) or clean-contaminated wounds (10 014 patients; aOR, 0.90; 95% CI, 0.73-1.12; P = .37) compared with a single dose. In this study, double-dose SAP with cefuroxime for patients weighing at least 80 kg was not consistently associated with a lower SSI rate.