Hematocrit increase with recombinant erythropoietin (rEPO) has been associated with increased progression of renal insufficiency in experimental models of renal mass reduction. The aim of the present study was to assess the effects of therapy with rEPO and various antihypertensives on the progression of chronic renal insufficiency and on arterial hypertension in an experimental model of renal mass reduction. Rats subjected to a two-thirds nephrectomy were randomly assigned to an untreated control group or to therapy with rEPO (subcutaneously, at an initial dose of 40 U/kg thrice weekly), rEPO plus verapamil (subcutaneously, 0.5 mg/kg/day), or rEPO plus enalapril (orally, 50 mg/l in the drinking water). Combining enalapril and rEPO therapy controlled systemic blood pressure (BP) and the increase in proteinuria. Glomerular injury, as assessed 16 weeks after renal ablation, was more marked in the animals treated with rEPO with or without either antihypertensive. The morphometric analyses showed greater glomerular tuft areas in the three groups receiving rEPO than in the controls. The glomerular tuft area was directly correlated with the rate of glomerulosclerosis. In about 11% of the rEPO-treated hypertensive rats, the lesions showed severe hypertensive vasculopathy; in the animals treated with rEPO plus enalapril, the lesions were less severe. We conclude that therapy with rEPO was associated to renal damage which could not be attenuated by enalapril despite controlling BP and proteinuria, and may have a nonhemodynamic cause. Therapy with rEPO might trigger lesions usually associated with severe arterial hypertension; concomitant therapy with enalapril attenuates hypertensive vasculopathy.