Plasma endothelin-1 (ET-1) levels were studied in 15 obese hypertensive (mean age 48.5 ± 3.9 years) and 15 obese normotensive men (mean age 49.5 ± 3.6 years) before and after weight loss due to an 800 kcal/day diet lasting 12 weeks. Circulating peptide concentrations were also assessed in nonobese hypertensive (n = 11) and normotensive men (n = 12). Baseline plasma ET-1 levels were similar in obese hypertensive (0.87 ± 0.22 pg/ml) and obese normotensive men (0.91 ± 0.30 pg/ml). In seven obese hypertensive men, caloric restriction normalized blood pressure levels (systolic: from 166.6 ± 8.1 to 145.0 ± 6.3 mmHg, P < 0.0001; diastolic: from 106.6 ± 5.1 to 89.1 ± 2.0 mmHg, P < 0.0001) and decreased body mass index (BMI) (from 33.4 ± 1.6 to 29.6 ± 2.1 kg/m², P < 0.002) and plasma ET-1 levels (from 0.93 ± 0.21 to 0.64 ± 0.26 pg/ml, P < 0.05). In the remaining obese hypertensive men (n = 8), blood pressure levels were not normalized by caloric restriction despite a significant decrease of BMI and plasma ET-1 levels (from 0.83 ± 0.23 to 0.60 ± 0.16 pg/ml, P < 0.04). Weight loss also significantly decreased BMI and ET-1 (from 0.91 ± 0.30 to 0.65 ± 0.19 pg/ml, P < 0.01) in obese normotensive men. Baseline ET-1 and fasting insulin levels were significantly correlated in obese hypertensive (r = 0.518, P < 0.05) and obese normotensive men (r = 0.535, P < 0.04). Changes in fasting insulin levels correlated with corresponding changes in plasma ET-1 levels after weight loss in both obese hypertensive (r = 0.558, P < 0.04) and obese normotensive men (r = 0.596, P < 0.02). Moreover, plasma peptide levels were significantly higher (P < 0.02) in obese hypertensive and obese normotensive men than in nonobese normotensive men (0.58 ± 0.28 pg/ml). In conclusion, this study shows that plasma ET-1 concentrations are increased in human obesity. The increase could depend on fasting insulin concentrations, abnormal peptide clearance, or both. Hypertension does not influence the behavior of plasma ET-1 levels in obese men.