Use of ibuprofen in patients with asymptomatic renal failure is known to produce acute renal toxicity. One of the manifestations is interstitial nephritis of which the pathogenic mechanism remains unclear. In the present study, this nephrotoxic syndrome was induced in rabbits by giving a single dose of uranyl nitrate, followed by consecutive doses of ibuprofen. This animal model thus allowed the assessment of renal functional and pathological changes associated with ibuprofen use in renal insufficiency. In these rabbits, the major abnormality appeared to be confined to the tubulointerstitial compartment. Microscopic examinations of the renal necropsy specimens showed tubular necrosis and interstitial lymphocytic infiltration. The histological finding of lymphocytic aggregation suggests that this nephrotoxic effect stems from a cytotoxic immune reaction in the interstitium. Moreover, levels of renal 2-arylpropionyl-CoA epimerase, a key enzyme involved in the metabolic inversion of ibuprofen, showed a significant reduction, which may result from the massive destruction of the tubular cells in these animals. These results support the premise that renal insufficiency is a prerequisite factor for ibuprofen-induced interstitial nephritis.