High high-density lipoprotein (HDL) levels protect against coronary artery disease (CAD) development. We hypothesized that patients with CAD and high HDL levels would have higher prevalence of other CAD risk factors compared with patients with CAD and normal HDL. We identified 41,982 patients from a single center with normal levels (40 to 60 mg/dl in men, 50 to 70 mg/dl in women) or high HDL levels (> or =70 mg/dl in men, > or =80 mg/dl in women) when last measured between January 2000 and April 2004. From this overall population, we characterized a cohort of 1,610 patients with CAD, including 98 patients with high HDL levels. We measured prevalence of traditional CAD risk factors by comparing these 98 patients with patients with CAD and normal HDL levels (n = 1,512). We performed manual chart review in patients (n = 196) matched 1:1 by age, gender, and HDL level to obtain further detail with regard to differences in family history and lifestyle factors. In patients with CAD, those with high HDL levels (98 of 1,610, 6.1%) were of similar age (71.1 vs 69.6 years, p = 0.23), had similar prevalence of hypertension (78.6% vs 88.7%, p = 0.30), lower levels of low-density lipoprotein (85.3 vs 90.9 mg/dl, p = 0.04) and triglycerides (87.1 vs 141.2 mg/dl, p <0.01), and a lower prevalence of diabetes (28.6% vs 38.4%, p = 0.05) compared with patients with normal HDL levels. In logistic regression models, patients with high HDL levels and CAD were less likely to have diabetes (adjusted odds ratio 0.60, 95% confidence interval 0.38 to 0.95, p = 0.03) or obesity (adjusted odds ratio 0.50, 95% confidence interval 0.25 to 0.99, p = 0.046) than patients with normal HDL levels and CAD. In conclusion, patients with high HDL and CAD had a similar or lower prevalence of traditional CAD risk factors compared with patients with normal HDL levels and CAD.