To investigate the interaction of metabolic and genetic factors in relation to PAI-1, genotype was determined at a 4G/5G polymorphism in the PAI-1 gene promoter and a Hind III RFLP of the PAI-1 gene in 189 Caucasian NIDDM patients. PAI-1 levels were equivalent in each genotype group and PAI-1 activity correlated with fasting insulin (r=0.45), triglyceride (r=0.39) body mass index (r=0.44), cholesterol (r=0.17) and glucose (r=0.15). The regression slope (B) of PAI-1 activity on triglycerides was steeper in the 4G/4G group than the other two groups: 4G/4G B = 0.91, r = 0.62; 4G/5G B = 0.36, r=0.27; 5G/5G B=0.31, r=0.29 (difference between slopes p=0.02) and the association between PAI-1 activity and glucose remained only in the 4G/4G group (r=0.35). These results confirm the association of PAI-1 levels with the features of insulin resistance and indicate that the association between PAI-1 levels and both triglyceride and glucose is influenced by genotype in the region of PAI-1 gene promoter.