Background: Pharmacokinetic data suggests that the intravenous form of n‐acetylcysteine (NAC) may be more effective than the oral formulation in preventing contrast induced nephropathy (CIN). NAC owing to its anti‐oxidant properties might be beneficial for patients with acute coronary syndromes (ACS) who are at increased risk for CIN. The aim of this prospective randomized, single‐center, double‐blind, placebo controlled trial (NCT00939913) was to assess the effect of high‐dose intravenous NAC on CIN in ACS patients undergoing coronary angiography and/or percutaneous coronary intervention (PCI). Methods: We randomized 398 ACS patients scheduled for diagnostic angiography ± PCI to an intravenous regimen of high‐dose NAC (1,200 mg bolus followed by 200 mg/hr for 24 hr; n = 206) or placebo (n = 192). The primary end‐point was incidence of CIN defined as an increase in serum creatinine concentration ≥25% above the baseline level within 72 hr of the administration of intravenous contrast. Results: There was no difference found for the primary end point with CIN in 16% of the NAC group and in 13% of the placebo group (p = 0.40). Change in serum cystatin‐C, a sensitive marker for renal function, was 0.046 ± 0.204 in the NAC group and 0.002 ± 0.260 in the control group (p = 0.07). Conclusion: In ACS patients undergoing angiography ± PCI, high‐dose intravenous NAC failed to reduce the incidence of CIN. © 2011 Wiley Periodicals, Inc.