Endothelin-1 (ET-1), a novel 21-amino acid vasoconstrictive peptide secreted by endothelial cells, has been thought to play a role in various forms of vascular disease. Diabetes mellitus is well known for its association with microvascular damage. To investigate whether ET-1 levels may be related to microangiopathy in diabetes mellitus, plasma ET-1 levels were measured in two groups of diabetic patients: A) 47 patients with non-insulin dependent diabetes mellitus (NIDDM) and retinopathy (28 M, 19 F; mean age 60.7+/-8.5 yrs) but without nephropathy (microalbuminuria < 30 mg/day) and hypertension (SBP < 140, DBP < 90 mmHg); group A was divided in three subgroups based on the severity of retinopathy: a) 16 with background retinopathy; b) 21 with pre-proliferative retinopathy; c) 10 with proliferative retinopathy. B) 8 patients with insulin-dependent diabetes mellitus (IDDM) recently diagnosed (6 M, 2 F; 16.4+/-3.8 yrs) without complications. C) 28 healthy subjects (HS) (16 M, 12 F; 47.8+/-11.8 yrs) as controls. In the NIDDM group the ET-1 concentration was significantly higher (17.3+/-2.4 pg/ml) than both in the HS (8+/-4.7 pg/ml) and IDDM patients (10.2+/-3.7 pg/ml) (p < 0.0001). In the subgroups with retinopathy the ET-1 levels were a) 15.1+/-4.3 pg/ml; b) 22.2+/-6.8 pg/ml and c) 16.6+/-5.1 pg/ml. These values were significantly elevated as compared to HS (p<0.001; p < 0.0001; p < 0.002, respectively), being the highest levels of ET-1 observed in the NIDDM patients with pre-proliferative retinopathy. In conclusion our study revealed that the ET-1 concentrations are elevated in NIDDM patients with retinopathy especially in those patients with pre-proliferative retinopathy.