Erythromycin is known to exacerbate cyclosporine nephrotoxicity. This has been attributed to the potential of erythromycin to reduce the hepatic microsomal metabolism and clearance of cyclosporine. Erythromycin may also be nephrotoxic. We tested the hypothesis that erythromycin may have direct effects on the renal vasculature which are additive or synergistic with the effects of cyclosporine. Sprague-Dawley rats were administered graded doses of either erythromycin, 2.5, 5, 7.5, and 10 mg/kg BW/min i. v. over consecutive 10-min intervals; cyclosporine, 1,2, 3, and 4 mg/kg BW/min i.v. over consecutive 10-min intervals; or both drugs simultaneously. In separate experiments, identical doses of erythromycin or cyclosporine were infused intravenously following acute unilateral renal denerva-tion. Infusion of erythromycin led to an initial decline in arterial blood pressure whereas infusion of cyclosporine resulted in a dose-related increase in arterial blood pressure. Despite these different systemic effects, each drug alone produced a striking decrease in renal blood flow. This effect was more pronounced when the drugs were infused concomitantly. The reduction in renal blood flow occurred in an additive manner as a direct consequence of increased renal vascular resistance. Prior renal denervation did not modify the response to either erythromycin or cyclosporine. These results demonstrate that cyclosporine-induced vasoconstriction is exacerbated by erythromycin and suggest that the decline in renal function observed in patients coadministered these drugs may be due in part to additive renovascular toxicity.