Background: Acute kidney injury (AKI) after heart surgery is associated with increased mortality. We sought to determine whether prophylactic perioperative administration of N-acetylcysteine (NAC) prevents postoperative AKI in patients with chronic kidney disease undergoing cardiac surgery (clinical trials.gov identifier NCT00211653). Methods: In this prospective, randomized, placebo-controlled, double-blinded clinical trial, 102 patients with chronic kidney disease who underwent heart surgery at the Minneapolis Veterans Affairs Medical Center were randomized to either NAC (n = 50) 600 mg PO twice daily or placebo (n = 52) for a total of 14 doses (3 preoperative). The primary outcome was maximum change in creatinine from baseline within 7 days after surgery. Secondary outcome was AKI (ie, >0.5 mg/dL or ≥25% increase in creatinine from baseline). Results: Creatinine increased in both groups (0.45 ± 0.7 mg/dL in NAC vs 0.55 ± 0.9 mg/dL in placebo, P = .53) and peaked on postoperative day 5. Acute kidney injury occurred in 41 patients (22 NAC vs 19 placebo, P = .44) by postoperative day 5, but persisted in only 14 (7 NAC vs 7 placebo, P = .94) by day 30. In multivariable analysis, perioperative NAC was unassociated with AKI (relative risk 1.2, 95% CI, 0.8-1.9, P = .34). Five patients (3 NAC vs 2 placebo, P = .68) underwent hemodialysis, and 5 (2 NAC vs 3 placebo, P = 1.0) died perioperatively. There was no difference in lengths of stay in the intensive care unit (4.9 ± 7 days in NAC vs 6.5 ± 9 days in placebo, P = .06) and the hospital (13.2 ± 13 days in NAC vs 16.7 ± 17 days in placebo, P = .12). Conclusion: Prophylactic perioperative NAC administration does not prevent AKI after cardiac surgery.