High-density lipoprotein (HDL) cholesterol has protective cardiovascular effects. We investigated the effect of baseline HDL cholesterol on the outcomes of patients who underwent drug-eluting stent implantation for acute coronary syndrome. Since March 2003, 1,032 consecutive patients were, according to their baseline HDL cholesterol level, included in a low HDL cholesterol group (n = 550, <40 mg/dl in men, <45 mg/dl in women, mean 32 +/- 7) or a high HDL cholesterol group (n = 482, >40 mg/dl in men, >45 mg/dl in women, mean 55 +/- 19). End points were death, Q-wave myocardial infarction, target lesion revascularization, and a composite of major adverse cardiac events at 30 days and 1 year. We assessed the relation between HDL cholesterol and end points. Patients with low HDL cholesterol more often had diabetes, a higher body mass index, higher triglyceride levels, and lower total cholesterol levels. Low-density lipoprotein cholesterol and statin treatment (98% in the 2 groups) were comparable. Incidences of mortality and major adverse cardiac events at 30 days were higher in the low than in the high HDL cholesterol group (p <0.001 and p = 0.002, respectively; chi-square analysis). At 1 year, more deaths occurred in the low HDL cholesterol group (p <0.001; chi-square analysis), as did major adverse cardiac events (p <0.001; chi-square analysis). Multivariate analysis showed low HDL cholesterol at baseline (hazard ratio 2.61, 95% confidence interval 1.33 to 5.12) to be a key predictor of major adverse cardiac events and death (hazard ratio 3.33, 95% confidence interval 1.15 to 10.0) at 1 year. In conclusion, regardless of baseline low-density lipoprotein cholesterol levels and statin therapy, additional strategies to increase HDL cholesterol should be evaluated in patients with acute coronary syndrome.