There is evidence that fenfluramine improves insulin action independently of its anorectic and weight-loss-inducing properties. Chronic d-fenfluramine also reduces hypothalamic noradrenergic tone, which correlates highly with hepatic glucose output. We report that chronic d-fenfluramine (5 mg · kg⁻¹ · day⁻¹) ameliorates insulin resistance induced by high-fat feeding. Insulin action was assessed in adult male rats at basal insulin levels and at hyperinsulinemia (∼140 mU/L with the euglycemic clamp technique). Hepatic glucose production, peripheral glucose disposal, and individual tissue glucose metabolism were determined from bolus injections of [³ H]-2-deoxyglucose and [¹⁴ C]glucose. Food intake was matched between groups. Basal glucose turnover was reduced 28% (P < .05) in fat-fed rats receiving d-fenfluramine (fat+fen). The glucose infusion rate to maintain euglycemia was 22.0 ± 1.1 mg · kg⁻¹ · min⁻¹ in the high-carbohydrate-fed rats, 8.2 ± 1.0 in fat-fed rats, and 15.1 ± 0.5 in the fat + fen group. Peripheral glucose disposal, reflecting measured skeletal muscle changes, was reduced by fat feeding (from 23.5 ± 1.0 to 13.8 ± 0.6 mg · kg¹ · min⁻¹) but was improved by d-fenfluramine (16.9 plusmn; 0.5, P < .05 vs. fat fed). Impaired suppression of hepatic glucose output by insulin, caused by fat feeding, was totally reversed by d-fenfluramine. Thus, d-fenfluramine counteracted diet-induced insulin resistance, with the predominant effect on the liver. We hypothesize that d-fenfluramine improves insulin action by reducing hypothalamic noradrenergic tone, which in turn reduces the neural drive to hepatic glucose output and improves the hepatic response to insulin.