Chronic treatment with selective alpha 1-inhibitors has a beneficial impact on plasma lipids and arterial pressure. To study the effect of selective alpha 1-inhibition on atherogenesis, gerbils and hamsters were fed rodent chow containing 0.2% cholesterol and 10% coconut oil (by weight). One group of each species received the selective alpha 1-inhibitor doxazosin (gerbil, 17 mg/kg/day; hamster, 11 mg/kg/day) in the diet. In gerbils treated for 6 weeks with doxazosin, plasma total cholesterol fell by 39% and very-low-density lipoprotein (VLDL) plus low-density lipoprotein (LDL) cholesterol by 52% compared with control levels. Plasma triglyceride and high-density lipoprotein (HDL) cholesterol were unaffected. In hamsters treated with doxazosin for 6 weeks, plasma total cholesterol, VLDL plus LDL cholesterols, and triglyceride were reduced by approximately 40% compared with hyperlipidemic controls. HDL cholesterol, mean arterial pressure, and heart rate were not significantly altered. Using en face preparations of the hamster aortic arch, intimal macrophage-derived foam cells were quantitated. Compared with controls, doxazosin reduced the number of intimal foam cells/mm2 by 71%. We suggest that selective alpha 1-inhibition reduces foam cell accumulation by lowering plasma lipids and/or by a direct effect on the arterial wall.