Published data on the association between prothrombin G20210A polymorphism and coronary artery disease (CAD) risk are inconclusive. To derive a more precise estimation of the relationship, a meta-analysis was performed. A total of 42 case-control studies including 15,041 cases and 21,507 controls were included in this meta-analysis. Overall, significantly elevated CAD risk was associated with prothrombin G20210A polymorphism (OR, 1.22; 95% CI 1.07-1.40; P=0.003) when 39 eligible studies were pooled into the meta-analysis. In the subgroup analysis, borderline statistically increased risk was found for myocardial infarction in 22 case-control studies (OR, 1.27; 95% CI 1.00-1.61; P=0.05). When stratified by ethnicity, significantly elevated risk was found in Europeans (OR, 1.19; 95% CI, 1.02-1.38; P=0.02). However, no statistical differences were found among Americans and Asians. In summary, this meta-analysis indicated that prothrombin G20210A allele is a low-penetrant risk factor for developing CAD in Europeans.