Coronary artery disease (CAD) is less common in African than Indian or White subjects and elevated plasminogen activator inhibitor (PAI)-1 levels may be a risk factor for CAD. Therefore, PAI-1 levels were measured in the three populations and related to the -675 PAI-1 4G/5G promoter genotype. PAI-1 levels and anthropometric variables were measured in 310 Indian, 269 White and 107 African subjects. The PAI-1 4G allele frequency was lower in the African (0.13) than Indian (0.54) or White (0.58) populations and explained the lower PAI-1 levels in African (41.5+/-25.1 versus 68.0+/-33.3 and 70.5+/-35.7 ng/ml, respectively; p<0.0001) subjects. Except for White subjects, PAI-1 levels were higher in those with metabolic syndrome or type 2 diabetes. PAI-1 genotype did not associate with either disorder. Metabolic syndrome-related factors had little influence on PAI-1 levels in White subjects but in African and Indians subjects these variables had a major influence on PAI-1 levels in those with the 5G/5G genotype but not in subjects with the 4G/4G genotype. Ethnic differences in PAI-1 levels are largely due to differences in the frequency of the 4G and 5G alleles at the -675 locus. In Indian and African, but not White populations, the ability of metabolic syndrome-related factors to influence PAI-1 levels is modulated by the -675 genotype.