Sprague-Dawley rats treated with cyclosporine (Cys) and appropriate controls were investigated with inulin, lithium and sodium clearances. It was found that Cys depressed glomerular filtration rate (GFR) and absolute proximal tubular reabsorption, while fractional proximal reabsorption was increased. As a normal proximal tubular reabsorptive capacity was found after volume expansion, and the intratubular pressure was normal, tubulotoxicity or obstruction of the tubular system by Cys was excluded. Increased fractional proximal reabsorption was also found with the occlusion time/transit time method. Intravenous Cys resulted in instantaneous renal functional changes qualitatively identical to those of prolonged Cys treatment. It was concluded that Cys nephrotoxicity is due to decreased ultrafiltration pressure, most probably due to a reversible spasm in the afferent glomerular arteriole.