Background American College of Cardiology/American Heart Association/European Society of Cardiology (ACC/AHA/ESC) guidelines gave fondaparinux a class I recommendation for use in patients with non-ST elevation acute coronary syndromes (NSTE-ACS) undergoing invasive or conservative strategy. Nadroparin is one of the common anticoagulants used in NSTE-ACS in China. Accordingly, this study compared the safety and efficacy between fondaparinux and nadroparin in patients with NSTE-ACS. Methods In this prospective, randomized, open-label, and single center study, a total of 300 patients with NSTE-ACS were randomized to receive either fondaparinux (group F, n=150, 2.5 mg/d) or nadroparin (group N, n=150, 0.1 ml/10 kg q12 h) for a mean of 4 days. The primary safety endpoint was the incidence of major or minor bleeding at 9 days that was not related to coronary artery bypass grafting (CABG). The primary efficacy endpoints included death, myocardial infarction, or recurrent ischemia at 9 days. All patients underwent a 180-day follow-up. Results Baseline characteristics were well matched between the two groups. There was a non-significant 28% relative risk reduction in the primary safety endpoint in group F compared with group N (4.7% vs. 6.7%, HR 0.72, 95% Cl 0.42-1.65, P=0.38). The primary efficacy endpoint was 8.0% in group F and 10.0% in group N (HR, 0.82, 95% Cl 0.54-1.71, P=0.49). The composite of the safety and efficacy endpoints at 9 days (10.0% vs. 16.0%, HR 0.61, 95% Cl 0.31-1.10, P=0.10), 30 days (14.0% vs. 17.9%, HR 0.72, 95% CI 0.47-1.16, P=0.21), or 180 days (18.7% vs. 27.3%, HR 0.65, 95% CI 0.38-1.11, P=0.11) showed a non-significant trend toward a lower value in group F. Conclusion Fondaparinux resulted in a nonsignificant risk reduction in patients with NSTE-ACS in both bleeding and ischaemic events during short- and long-term follow-up compared with nadroparin. Chin Med J 2011;124(6):879-886