Background: Acute renal failure after major surgery is associated with significant mortality and morbidity that theoretically may be attenuated by N-acetylcysteine. Design: Meta-analysis of relevant studies sourced from the Cochrane Controlled Trial Register (2007 issue 4), EMBASE, and MEDLINE databases (1966 to February 1, 2008) without language restriction. Setting & Population: Adult patients undergoing major surgery without the use of radiocontrast. Selection Criteria for Studies: Randomized controlled studies comparing N-acetylcysteine with a placebo perioperatively. Data Analysis: Categorical variables are reported as odds ratio (OR) with 95% confidence interval (Cl), and continuous variables are reported as weighted-mean-difference (WMD) with 95% CI. Outcome Measures: Effects of N-acetylcysteine on mortality and acute renal failure requiring dialysis were the main outcomes of interest. Additional outcome measures included an incremental increase in serum creatinine concentration greater than 25% above baseline, surgical reexploration for bleeding, amount of allogeneic blood transfusion, and length of intensive care unit stay. Results: 10 studies involving a total of 1,193 adult patients undergoing major surgery were considered. N-Acetylcysteine use was not associated with a decrease in mortality (OR, 1.05; 95% CI, 0.58 to 1.92), acute renal failure requiring dialysis (OR, 1.04; 95% CI, 0.45 to 2.37), incremental increase in serum creatinine concentration greater than 25% above baseline (OR, 0.84; 95% CI, 0.64 to 1.11), or length of intensive care unit stay (WMD in days, 0.46; 95% CI, -0.43 to 1.36). N-Acetylcysteine did not appear to increase the risk of surgical reexploration for bleeding (OR, 1.16; 95% CI, 0.57 to 2.38) or amount of allogeneic blood transfusion required (WMD in units, 0.31; 95% CI, -0.21 to 0.84). Limitations: Most studied patients had cardiac surgery and normal renal function preoperatively. Conclusions: There is no current evidence that N-acetylcysteine used perioperatively can alter mortality or renal outcomes when radiocontrast is not used. Am J Kidney Dis 53:33-40. 0 2008 by the National Kidney Foundation, Inc.