Agonists active at I₁-imidazoline receptors (I₁R) not only lower blood pressure but also ameliorate glucose intolerance, insulin resistance, and hyperlipidemia with long-term treatment. We sought to determine the possible mechanism for the lipid-lowering actions of imidazolines in a model of metabolic Syndrome X, the spontaneously-hypertensive obese (SHROB) rat. The acute actions of moxonidine and rilmenidine, selective I₁R agonists, were compared to a specific α₂-adrenergic receptor agonist, guanabenz, with and without selective receptor blockers. Moxonidine and rilmenidine rapidly reduced plasma triglyceride (20±4% and 21±5%, respectively) and cholesterol (29±9% and 27±9%). In contrast, the specific α₂-adrenergic receptor agonist guanabenz failed to reduce plasma lipids. Blocking experiments showed that moxonidine’s actions were mediated by I₁R and not α₂-adrenergic receptors. To evaluate a hepatic site of action, radioligand binding studies with liver plasma membranes confirmed the presence of I₁R. Intraportal moxonidine reduced plasma triglycerides by 23±3% within 10 min. Moxonidine inhibited hepatic triglyceride secretion by 75% compared to vehicle treatment. Tracer studies with ²H₂O suggested that moxonidine inhibits de novo fatty acid synthesis. Thus, activation of I₁R lowers plasma lipids, with the main site of action probably within the liver to reduce synthesis and secretion of triglycerides. More selective I₁R agonists might provide monotherapy for hyperlipidemic hypertension.