This study tested the hypothesis that the adverse effects of cyclosporine (Cy) are accelerated in animals with induced hypertension. Four groups of rats were unilaterally nephrectomized at 5 weeks of age. Two weeks later, two of these groups received implantations of Silastic strips impregnated with deoxycorticosterone acetate (DOCA) and were maintained on 1% saline (DOCA-NaCl); the other two groups served as sham controls. Daily injections of Cy (20 mg/kg) were given to one DOCA-NaCl and one control group. During the initial 3 days, the Cy/DOCA-NaCl treated rats displayed a significant increase in systolic arterial pressure (SAP), but their SAP did not increase significantly thereafter. Cy/DOCA-NaCl treatment caused severe nephrotoxicity 18 days after initiation of treatment, but neither cyclosporine nor DOCA-NaCl treatment alone resulted in morphological renal damage. In Cy/DOCA-NaCl rats, the interstitial spaces between renal tubules were dramatically increased in size and contained abundant bundles of collagenous fibres, deposits of immunoreactive laminin, and infiltrates of mononuclear cells. In a second experiment, bilateral renal denervation prior to treatment did not lessen the Cy-induced renal damage. These results indicate that in the DOCA-NaCl rat, Cy treatment damages the renal cortex in a pattern similar to that observed in humans treated chronically with Cy. Further, the results indicate that an absence of renal innervation does not decrease the nephrotoxic effects of Cy in this rapid onset model.