Background- Substantial evidence-practice gaps exist in the management of acute coronary syndromes (ACS) in China. Clinical pathways are tools for improving ACS quality of care but have not been rigorously evaluated. Methods and Results- Between October 2007 and August 2010, a quality improvement program was conducted in 75 hospitals throughout China with mixed methods evaluation in a cluster randomized, controlled trial. Eligible hospitals were level 2 or level 3 centers routinely admitting > 100 patients with ACS per year. Hospitals were assigned immediate implementation of the American Heart Association/American College of Cardiology guideline based clinical pathways or commencement of the intervention 12 months later. Outcomes were several key performance indicators reflecting the management of ACS. The key performance indicators were measured 12 months after commencement in intervention hospitals and compared with baseline data in control hospitals, using data collected from 50 consecutive patients in each hospital. Pathway implementation was associated with an increased proportion of patients discharged on appropriate medical therapy, with nonsignificant improvements or absence of effects on other key performance indicators. Conclusions- Among hospitals in China, the use of a clinical pathway for the treatment of ACS compared with usual care improved secondary prevention treatments, but effectiveness was otherwise limited. An accompanying process evaluation identified several health system barriers to more successful implementation. Clinical Trial Registration- URL: http://www.anzctr.org.au/default.aspx. Unique identifier: ACTRN12609000491268.