Male Fischer 344 rats classified as young (2-4 months), middle-aged (12-15 months) and aged (22-25 months) were administered 600 mg/kg acetaminophen (APAP) IP. Rats were killed 6 and 12 h after dosing, and renal damage evaluated by blood urea nitrogen (BUN) levels and histopathology. In addition, plasma levels of APAP and its sulfate and glucuronide conjugates were determined after 6 h. There was no evidence of renal damage in any age group 6 h after APAP. While no nephrotoxicity was present in young animals after 12 h, BUN was elevated 94% and 214% in middle-aged and aged rats, respectively, compared to young animals. At 12 h, APAP-induced renal lesions were more severe in aged rats compared to middle-aged animals. APAP-induced renal damage, as judged by BUN and histopathology, was not altered in young or middle-aged rats following unilateral nephrectomy. Six hours after APAP, both the middle-aged and aged animals had significantly higher plasma levels of APAP and APAP glucuronide compared to young rats. There were similar amounts of the sulfate conjugate in the plasma of each age group. This suggests pharmacokinetic differences could contribute to the age-related increased susceptibility of male Fischer 344 rats to APAP-induced nephrotoxicity.