Hyperlipidemic Imai rats spontaneously develop hypercholesterolemia, proteinuria and glomerulosclerosis. The aim of the present study was to clarify whether two different antihypertensive regimens (enalapril and a combination of reserpine, hydralazine and hydrochlorothiazide) would offer similar degrees of protection against glomerular injury in male hyperlipidemic Imai rats. Group 1 (n = 4) received no specific therapy. Group 2 (n = 4) was treated with enalapril at a dose of 50 mg/l in drinking water starting at 6 weeks of age. Group 3 (n = 5) was treated with the triple drug regimen (reserpine 5 mg/l, hydralazine 80 mg/l and hydrochlorothiazide 25 mg/l in drinking water). Body weight, blood pressure, urinary protein, serum albumin, cholesterol, BUN and serum creatinine were checked and compared among groups. Although enalapril and triple drug therapy were almost equally effective in controlling systemic hypertension, there were striking differences between the two treated groups in proteinuria, hypercholesterolemia and glomerular injury. Enalapril treatment significantly reduced proteinuria (731 ± 23 vs. 256 ± 144 mg/kg/day at 36 week; p < 0.005) and hypercholesterolemia (264 ± 17 vs. 104 ± 17 mg/dl at 38 weeks; p < 0.001). Triple drug therapy failed to prevent the development of proteinuria (909 ± 75 mg/kg/day at 38 weeks) and hypercholesterolemia (330 ± 61 mg/dl at 38 weeks). The glomerulosclerosis index was significantly higher in untreated control rats (229 ± 65) and in triple drug-treated rats (218 ± 59) than in the enalapril-treated group (24 ± 12; p < 0.05 and p < 0.01, respectively). These results, showing a sharp contrast between the effect of antihypertensive therapy on blood pressure and that on renal injury, suggest that even in hyperlipidemic Imai rats, other factors are involved in renal protection besides reduction of systemic blood pressure.