We determined the effect of estrogen and progesterone on plasma cholesterol and lipoprotein cholesterol concentrations and on arterial lesions in 24 ovariectomized and hysterectomized baboons fed a high-cholesterol/high-saturated-fat diet These baboons were divided into four groups: untreated control (C); estrogen, 100 μg/kg/week injected l.m. (E); progesterone, 3 mg/kg/day (P); and estrogen plus progesterone (E+P). The treatment regimen continued for 18 months. Cholesterol levels in plasma and lipoproteins were measured before hormone treatment and at 3, 10, and 18 months of treatment Postheparin plasma lipoprotein lipase (LPL) activity was also measured during the treatment After 18 months of hormone treatment, baboons were necropsied and arterial lesions were measured. Hormone treatment significantly influenced plasma cholesterol (P>C>[E+P]>E) and very low density lipoprotein plus low density lipoprotein (VLDL+LDL) cholesterol (P>C> [E+P] >E), with very little effect on high density lipoprotein (HDL) cholesterol concentration. The E+P group had a significantly higher HDL cholesterol concentration than did the P group. The (VLDL+LDL)/HDL cholesterol ratios in the E and E+P groups were significantly lower than those in the P and C groups. LPL activities were significantly lower in the E group compared with those in the E+P and P groups. Hormone treatment significantly influenced lesions in four (innominate, carotid, iliac, and abdominal aorta) of seven arteries. The P group had the most fatty streaks, and the E+P group had the least Multiple regression analysis suggested that hormone treatment influenced arterial lesions, both through effects on VLDL+LDL cholesterol and (VLDL+LDL)/HDL cholesterol ratio and through an effect independent of lipoproteins.