A high perioperative inspiratory oxygen fraction (80%) has been recommended to prevent postoperative wound infections. However, the most recent and one of the largest trials, the PROXI trial, found no reduction in surgical site infection, and 30-day mortality was higher in patients given 80% oxygen. In this follow-up study of the PROXI trial we assessed the association between long-term mortality and perioperative oxygen fraction in patients undergoing abdominal surgery. From October 8, 2006, to October 6, 2008, 1386 patients underwent elective or emergency laparotomy and were randomized to receive either 80% or 30% oxygen during and for 2 hours after surgery. The follow-up date was February 24, 2010. Survival was analyzed using Kaplan-Meier statistics and the Cox proportional hazards model. Vital status was obtained in 1382 of 1386 patients after a median follow-up of 2.3 years (range 1.3 to 3.4 years). One hundred fifty-nine of 685 patients (23.2%) died in the 80% oxygen group compared to 128 of 701 patients (18.3%) assigned to 30% oxygen (HR, 1.30 95% confidence interval, 1.03 to 1.64, P = 0.03). In patients undergoing cancer surgery, the HR was 1.45; 95% confidence interval, 1.10 to 1.90; P = 0.009; and after noncancer surgery, the HR was 1.06; 95% confidence interval, 0.69 to 1.65; P = 0.79. Administration of 80% oxygen in the perioperative period was associated with significantly increased long-term mortality and this appeared to be statistically significant in patients undergoing cancer surgery but not in noncancer patients.