This study assessed the potential cost-effectiveness of high (80-100%) vs low (21-35%) fraction of inspired oxygen (FiO2) at preventing surgical site infections (SSIs) after abdominal surgery in Nigeria, India, and South Africa. Decision-analytic models were constructed using best available evidence sourced from unbundled data of an ongoing pilot trial assessing the effectiveness of high FiO2, published literature, and a cost survey in Nigeria, India, and South Africa. Effectiveness was measured as percentage of SSIs at 30 days after surgery, a healthcare perspective was adopted, and costs were reported in US dollars ($). High FiO2 may be cost-effective (cheaper and effective). In Nigeria, the average cost for high FiO2 was $216 compared with $222 for low FiO2 leading to a-$6 (95% confidence interval [CI]:-$13 to-$1) difference in costs. In India, the average cost for high FiO2 was $184 compared with $195 for low FiO2 leading to a-$11 (95% CI:-$15 to-$6) difference in costs. In South Africa, the average cost for high FiO2 was $1164 compared with $1257 for low FiO2 leading to a-$93 (95% CI:-$132 to-$65) difference in costs. The high FiO2 arm had few SSIs, 7.33% compared with 8.38% for low FiO2, leading to a-1.05 (95% CI:-1.14 to-0.90) percentage point reduction in SSIs. High FiO2 could be cost-effective at preventing SSIs in the three countries but further data from large clinical trials are required to confirm this.