Background: Four randomized trials have evaluated the impact of supplemental perioperative oxygen on the incidence of surgical site infections (SSIs), with mixed results. The objectives of this meta-analysis were: (1) To evaluate further the effect of supplemental perioperative oxygen on SSIs after colorectal surgery; and (2) to generate a strategy for future studies to determine definitively the value of this intervention. Methods: We conducted a MEDLINE search to identify randomized trials of supplemental perioperative oxygen with a primary endpoint of SSI. Fixed-effects and random-effects models were employed, and the null association was tested for each. Tests also were performed for heterogeneity and publication bias. Results: Four studies were identified that satisfied the search criteria. The total number of patients was 943, of whom 477 received supplemental oxygen and 466 served as controls. The pooled risk ratio (RR) for SSI favored the patients who received supplemental oxygen (RR = 0.68; 95% confidence interval [CI] 0.49, 0.94), but this difference was not maintained with a random-effects model (RR = 0.73; 95% CI 0.42, 1.28; p = 0.27). Heterogeneity was present among the studies. There was no evidence of publication bias. Conclusions: Supplemental perioperative oxygen is associated with a lower risk of SSI in patients undergoing colorectal surgery. The heterogeneity among the individual reports may be secondary to differences in study protocols.