The pathogenesis of coronary artery disease (CAD) is closely associated with inflammation, in which human leukocyte antigens (HLA), especially HLA-DR molecules, play important roles. However, whether various HLA-DRB1 alleles can contribute differing susceptibility to CAD has not been elucidated. In this study, we demonstrated a significantly lower frequency of HLA-DRB1*12:02:01 in the CAD group (9.82%) than in controls (18.22%) after age adjustment (odds ratio [OR] = 0.489, p = 0.0036). Logistic regression analysis indicated that carriers of HLA-DRB1*12:02:01 exhibited a lower risk of CAD events after adjustment for age, gender, and other confounders (p = 0.014, OR = 0.526[95% confidence interval 0.314-0.878]). The female carriers of HLA-DRB1*12:02:01 exhibited a much lower risk of CAD events both before (OR = 0.424, p = 0.0387) and after age adjustment (OR = 0.302, p = 0.0058). In another female cohort, the frequency of HLA-DRB1*12:02:01 also differed between the female CAD group (8.23%) and the female controls (18.75%; OR = 0.389, p = 0.0116). Further analysis indicated that HLA-DRB1*12:02:01 was not frequent in participants with premature CAD or more diseased blood vessels. In summary, our data demonstrate that HLA-DRB1*12: 02:01 plays a protective role against CAD in southern Han Chinese, especially in females. The mechanism behind the protective effect requires further exploration. (C) 2012 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.