OBJECTIVE We sought to assess the effect of naproxen versus placebo on prevention of atrial fibrillation after coronary artery bypass graft (CABG) surgery. METHODS In this randomized, double-blind, placebo-controlled, single-center trial of 161 consecutive patients undergoing CABG surgery, patients received naproxen 275 mg every 12 hours or placebo at the same dosage and interval over 120 hours immediately after CABG surgery. The primary outcome was the occurrence of atrial fibrillation in the first 5 postoperative days. RESULTS The incidence of postoperative atrial fibrillation was 15.2% (12/79) in the placebo versus 7.3% (6/82) in the naproxen group (P=.11). The duration of atrial fibrillation episodes was significantly lower in the naproxen (0.35 hours) versus placebo group (3.74 hours; P=.04). There was no difference in the overall days of hospitalization between placebo (17.23±7.39) and naproxen (18.33±9.59) groups (P=.44). Intensive care unit length of stay was 4.0±4.57 days in the placebo and 3.23±1.25 days in the naproxen group (P=.16). The trial was stopped by the data monitoring committee before reaching the initial target number of 200 patients because of an increase in renal failure in the naproxen group (7.3% vs 1.3%; P=.06). CONCLUSIONS Postoperative use of naproxen did not reduce the incidence of atrial fibrillation but decreased its duration, in a limited sample of patients after CABG surgery. There was a significant increase in acute renal failure in patients receiving naproxen 275 mg twice daily. Our study does not support the routine use of naproxen after CABG surgery for the prevention of atrial fibrillation.