To clarify the pathogenesis of focal and segmental glomerulosclerosis, we investigated the effect of ovariectomy in hypercholesterolemic female Imai rats. At 5 weeks of age, control female (group 1) and control male rats (group 3) were sham-operated, female rats (group 2) were ovariectomized and male rats (group 4) were castrated. Body weight, blood pressure, urinary protein and serum constituents were checked every 2 months from 2 through 12 months of age. All groups were studied morphologically at 6 months of age and further female groups (1 and 2) studied at 12 months. Both control female and control male rats developed marked proteinuria, to a significantly greater extent in the male rats. Castration reduced proteinuria, while ovariectomy did not influence it and there were no significant differences in proteinuria among the control females, the ovariectomized females and the castrated males. Control male rats had significantly lower serum albumin levels, higher cholesterol levels and a significantly greater impairment of renal function in blood urea nitrogen (BUN) levels than did the control female rats at 6 months. Castration significantly increased serum albumin levels and lowered BUN levels, while ovariectomy did not basically influence these values in the female rats. The glomerulosclerosis index at 6 months of age was significantly higher in the control males than in the control females. Castration attenuated glomerular injury, while ovariectomy aggravated glomerular injury to the same levels as found in the castrated males. This aggravating effect of ovariectomy observed at 6 months, however, disappeared at 12 months. These results suggested that sex-related factors regulated by the ovaries may play an inhibitory role in the development of glomerulosclerosis before 6 months of age, but not thereafter, in hypercholesterolemic female Imai rats.