Elevated total plasma homocysteine is an established risk factor for cardiovascular disease. Experimental evidence suggests that non-protein-bound free homocysteine is particularly hazardous to the vascular endothelium. This study evaluates the predictive role of free plasma homocysteine levels on cardiovascular endpoints in patients with acute coronary syndrome (ACS). In a cohort of 379 hospitalized patients with a diagnosis of myocardial infarction or unstable angina pectoris, total and free plasma homocysteine levels were measured by high performance liquid chromatography. The patients were followed for a median 2.7 years. The primary endpoint was a composite of cardiovascular death, myocardial infarction and stroke during follow-up. Stepwise Cox regression was used for multivariate analysis. Primary outcome events occurred in 82 patients (22%) with a median time to event of 6 months. The unadjusted hazard ratio for a free homocysteine level >4.11 micromol/L was 2.16 (95% confidence intervals [CI] 1.36 to 3.42) compared with the 4 lower quintiles. After adjusting for the covariates the hazard ratio was 2.25 (95% CI 1.41 to 3.58, p = 0.01). Compared with the lower 4 quintiles, patients with a total homocysteine level >22.4 micromol/L had a 2.09-fold higher risk (95% CI 1.31 to 3.35) for an event during follow-up. Adjusted for age, discharge diagnosis, serum creatinine, history of atherothrombotic events, and diabetes mellitus, the adjusted hazard ratio was 1.37 (95% CI 0.83 to 2.25, p = 0.22). In conclusion, plasma free homocysteine levels >4.11 micromol/L are a significant and independent risk factor for recurrent cardiovascular events in patients hospitalized for ACS, although total plasma homocysteine levels have no predictive value.