Acute renal failure after major surgery is associated with significant mortality and morbidity that theoretically may be attenuated by N-acetylcysteine. 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. Adult patients undergoing major surgery without the use of radiocontrast. Randomized controlled studies comparing N-acetylcysteine with a placebo perioperatively. Categorical variables are reported as odds ratio (OR) with 95% confidence interval (CI), and continuous variables are reported as weighted-mean-difference (WMD) with 95% CI. 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. 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). Most studied patients had cardiac surgery and normal renal function preoperatively. There is no current evidence that N-acetylcysteine used perioperatively can alter mortality or renal outcomes when radiocontrast is not used.