Matrix metallopeptidase-9 (MMP-9) plays a pivotal role in vascular remodeling and development of atherosclerotic lesion. The potentially functional MMP-9 polymorphisms may contribute to the susceptibility of coronary artery disease (CAD). A case-control study composed of 762 CAD cases and 555 CAD-free controls was conducted in a Chinese population to investigate the association between the MMP-9 -1562 C>T, R279Q, P574R and R668Q polymorphisms and CAD risk. It was found that the variant genotypes of R279Q, P574R and R668Q were associated with a non-significant decreased risk of CAD when compared with their wild-type genotypes, respectively, Furthermore, compared with those without any variant genotypes for these four nonsynonymouse loci, individuals carrying all four variant genotypes (-1562 CT/TT, 279 RQ/QQ, 574 PR/RR and 668 RQ/QQ) had a 51% decreased risk of CAD (adjusted OR = 0.49; 95% CI = 0.26-0.95, P = 0.033). Although no significant main effects were observed for MMP-9 -1562 C>T locus on CAD risk, variant genotypes of -1562 C>T were associated with a 2.53 increased risk of CAD in subjects with diabetes mellitus (DM) (95% CI = 1.18-5.45, P = 0.018). In CAD cases, variant genotypes of -1562 C>T were associated with a significantly increased risk of MI (adjusted OR, 1.48, 95% CI, 1.01-2.20, P = 0.048). These findings suggest that MMP-9 R279Q, P574R and R668Q may have combined effect in the occurrence of CAD and -1562 CT/TT genotypes may contribute to CAD in diabetics and MI in CAD patients.