Age-related differences in susceptibility to cephaloridine nephrotoxicity were evaluated in male Fischer-344 rats. Rats, 2.5, 4, 10-12 and 27-29 months old, were administered a single intraperitoneal dose of cephaloridine and renal function evaluated 24 h later. Susceptibility to cephaloridine-induced nephrotoxicity was age-related. Older rats (10-12 and 27-29 months) were the most susceptible to cephaloridine nephrotoxicity as indicated by a dose-related increase in relative kidney weight, elevation in blood urea nitrogen concentrations and a diminished capacity of renal cortical slices to accumulate the organic anion, p-aminohippurate (PAH) and the organic cation, tetraethylammonium (TEA). Impaired renal function following cephaloridine treatment was not detected in 2.5-month-old, apparent to a slight extent in 4-month-old, and most pronounced in 10-12- and 27-29-month-old rats. Serum and renal cortical concentrations of cephaloridine tended to be greater in older rats compared to that of young adults. Thus, the enhanced susceptibility of older rats to cephaloridine nephrotoxicity may be related in part to the increased renal cortical accumulation of cephaloridine.