The nephrotoxic property of cyclosporin A (Cy A) was investigated in groups of Sprague-Dawley rats given various dose regimes over a 21-day period. Impairment of glomerular filtration was clearly evidenced by elevated serum urea and creatinine levels and by reduced urea clearance rates. There were also dose-related increases in urinary N-acetyl-beta-D-glucosaminidase activity. These biochemical changes were accompanied by structural evidence of damage to the straight segment of the proximal tubule; this consisted of varying degrees of cytoplasmic vacuolation, due to dilatation of both smooth and rough endoplasmic reticulum, and, at the highest dose tested, occasional individual cell necrosis and desquamation. Ultrastructural examination revealed additional dose-related abnormalities affecting the entire length of the proximal tubule, including increased lysosome production and the formation of cytosegresomes and myeloid bodies.