To detemine the therapeutic effect of the carinitine palmitoyltransferase I (CPT-I) inhibitor, etomoxir, eight hospitalized obese non-insulin-dependent diabetes mellitus (NIDDM) patients were studied (body mass index [BMI], 28.7±1.3 kg/m 2; age, 54±8 years [means±SE]) at baseline (placebo= t1), and after oral etomoxir (50 mg/d= t2, 100 mg= 3, 150 mg= t4, 200 mg= t5, placebo= t6). Fasting blood glucose (mmol/L), triglycerides (mmol/L), cholesterol (mmol/L), free fatty acids (μmol/L), β-hydroxybutyrate (μmol/L), and alanine aminotransferase (GPT, U/L) were determined (t1 to t6), as were glucose utilization (M value; indirect calorimetry) and hepatic glucose production during a 10 mU/kg· min euglycemic clamp (t1 and t4). A dose-dependent decrease was induced by etomoxir in fasting blood glucose (t1 to t5: 9.5±0.7, 8.7±1.0, 8.3±1.1,[Pv t1<. 05], 7.8±0.9,[Pv t1<. 01], 7.9±1.1 [Pv t1<. 05]), which was reversible in t6 (9.9±1.1). Mean plasma lipids were reduced (t1 v t5) for triglycerides (− 54%, Pv t1<. 01), cholesterol (− 24%, Pv t1<. 05), and β-hydroxybutyrate (− 44%, Pv t2<. 01), while free fatty acids increased by 52%(Pv t1<. 05), as did GPT (t1: 17±3; t5: 32±7 U/L [Pv t 1<. 01]). In parallel, hepatic glucose production (mg/min· m 2) decreased (t 1 t 4: 88±7 73±8 [P v t1<. 05]), whereas M values,(263±27 268±29 mg/min· m 2), carbohydrate oxidation (90±8 74±9 mg/min· m 2), and fat oxidation (21±7 28±6 mg/min· m 2) remained unchanged during the 10-mU/kg· min euglycemic clamp. It is concluded that etomoxir reduces hepatic glucose production, fasting blood glucose, and lipidemia—triglycerides, cholesterol, and β-hydroxybutyrate included—without affecting glucose utilization (M value) during a hyperinsulinemic euglycemic clamp. Such a pharmacologic profile might be helpful in treating hyperlipidemic NIDDM.