OBJECTIVES: Does marijuana smoking increase the risk of surgical site infection (SSI) after open reduction and internal fixation of fractures? METHODS: Design: Retrospective. Setting: Single academic level 1 trauma center in Southern California. Patient Selection Criteria: Adult patients who underwent open treatment for closed fractures between January 2009 and December 2021, had hardware placed, and had at least 6 months of postoperative follow-up. Outcome Measures and Comparisons: Risk factors associated with the development of SSI were compared between current inhalational marijuana users and nonmarijuana users. RESULTS: Complete data were available on 4802 patients after exclusion of 82 who did not have a complete variable set. At the time of surgery, 24% (1133 patients) were current users of marijuana. At the final follow-up (minimum 6 months), there was a 1.6% infection rate (75 patients). The average age of the infection-free group was 46.1 ± 23.1 years, and the average age of the SSI group was 47.0 ± 20.3 (P = 0.73) years. In total, 2703 patients (57%) in the infection-free group were male compared with 48 (64%) in the SSI group (P = 0.49). On multivariate analysis, longer operative times (OR 1.002 [95% CI, 1.001–1.004]), diabetic status (OR 2.084 [95% CI, 1.225–3.547]), and current tobacco use (OR 2.493 [95% CI, 1.514–4.106]) (P < 0.01 for all) were associated with an increased risk of SSI; however, current marijuana use was not (OR 0.678 [95% CI, 0.228–2.013], P = 0.48). CONCLUSIONS: Tobacco use, diabetes, and longer operative times were associated with the development of SSI after open reduction and internal fixation of fractures; however, marijuana smoking was not shown to be associated with the development of SSI. LEVEL OF EVIDENCE: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.