Background: Most surgical prophylaxis guidelines recommend a 3-g cefazolin intravenous dose in patients weighing ≥ 120 kg. However, this recommendation is primarily based on pharmacokinetic studies rather than robust clinical evidence. This study aimed to compare the prevalence of surgical site infections (SSIs) in obese and non-obese patients (body mass index ≥ 30 kg/m2 and < 30 kg/m2), and those weighing ≥ 120 kg and < 120 kg, who received 2- g cefazolin preoperatively. Methods: A retrospective case-control study was conducted in adult elective surgical patients. Patients receiving 2- g cefazolin were grouped as obese and non-obese, and by weight (≥ 120 kg or < 120 kg). The 90-day prevalence of SSI and potential contributing factors were investigated. Results: We identified 152 obese (median 134 kg) and 152 non-obese control (median 73 kg) patients. Baseline characteristics were similar between groups, except for an increased prevalence in the obese group of diabetes (35.5% vs 13.2%; p < 0.001) and an American Society of Anaesthesiologists Score of 3 (61.8% vs 17.1%; p < 0.001). While not statistically significant, the prevalence of SSI in the obese group was almost double that in the non-obese group (8.6% vs 4.6%; p = 0.25) and in patients weighing ≥ 120 kg (n = 102) compared to those weighing < 120 kg (n = 202) (9.8% vs 5.0%; p = 0.17). Conclusion: The prevalence of SSI was not significantly increased in obese patients, or those weighing ≥ 120 kg, who received cefazolin 2- g prophylactically; however, trends toward an increase were evident. Large-scale randomised trials are needed to examine whether a 2-g or 3-g cefazolin is adequate to prevent SSI in obese (and ≥ 120 kg) individuals.