The rationale for hyperoxygenation in controlling surgical site infection (SSI) has been described in many studies yet has not been defined clearly. Some studies in colorectal surgery have reported beneficial effects, whereas studies in gynecologic surgery have reported either no effect or a deleterious effect. This study assessed the effectiveness of hyperoxygenation on the reduction of SSI in patients undergoing emergency abdominal surgery. Eligible patients were assigned randomly to two groups (study group, 80% oxygen or control group, 30% oxygen). The patients in the study group received 80% oxygen and the patients in the control group received 30% oxygen intra-operatively and for two hours after surgery. Arterial blood gas analysis was done after resuscitation, at the end of the surgery, and at two hours after extubation. All patients were assessed for SSI, post-operative nausea and vomiting, and respiratory complications. Patients were followed post-operatively for 14 days. Surgical site infection was diagnosed according to U.S. Centers for Disease Control and Infection (CDC) criteria and by aerobic wound cultures. After exclusion, 85 patients in the control group and 93 patients in the study group were analyzed. There was no difference for baseline, intra-operative, and post-operative characteristics between the two groups, except for higher oxygen saturation at closure and two hours post-operatively, in the 80% group (p = 0.01). Surgical site infection occurred in 29 patients (34.11%) in 30% fraction of inspired oxygen (FO) group and in 19 patients (20.43%) in 80% FO group (p = 0.04). The risk of SSI was 59% lower in the 80% FO group (adjusted odds ratio, 0.41; 95% confidence interval [CI], 0.19-0.88 vs. the 30% FO group). There were no differences in post-operative nausea and vomiting and respiratory complications between the two treatment groups. Administration of 80% peri-operative hyperoxygenation in emergency abdominal surgery reduces SSI and is a cost-effective method.