BACKGROUND: Plasminogen activator inhibitor (PAI)-1, a key regulator of fibrinolysis, is associated with increased risk of coronary heart disease (CHD) and is a potential therapeutic target for CHD. However, the relationship between PAI-1 and the most common diabetic microvascular complication, retinopathy, is unclear. The purpose of this study was to assess the relationship between PAI-1 activity and both retinopathy and CHD in type 2 diabetes. METHODS AND RESULTS: We determined PAI-1 activity and both retinopathy (assessed by masked grading of 3-field retinal photographs) and CHD status (assessed by ECG and standard questionnaires) in 147 men and women with type 2 diabetes, mean age (SD) 64 (7) years, in a cross-sectional setting. Plasma PAI-1 activity was inversely associated with prevalent retinopathy (P=0.006) and severity of retinopathy (P=0.022), and was associated with lower risk of diabetic retinopathy, independent of major retinopathy risk factors (duration of diabetes and HbA1c) and determinants of PAI-1 (obesity and triglyceride level) (OR 0.74 [0.60 to 0.92], P=0.006). Conversely, higher plasma PAI-1 activity was independently associated with greater risk of CHD, after adjusting for the major CHD risk factors and determinants of PAI-1 (OR 1.31 [1.06 to 1.62], P=0.001). CONCLUSIONS: These data support mounting evidence that a higher PAI-1 plasma level is independently associated with a lower risk of retinopathy but a higher risk of CHD in type 2 diabetes.