Cortical tubular necrosis induced by either aspirin (300 mg/kg) or oxyphenbutazone (444 mg/kg) was reduced if probenecid (300 mg/kg) was administered at the same time. The prior administration of aspirin (600 mg/kg) reduced the tubular necrosis that follows administration of oxyphenbutazone (444 mg/kg) alone, thus demonstrating that some degree of cross-tolerance between the two drugs occurs. Phenacetin pretreatment (597 mg/kg) was less effective, while paracetamol (503 mg/kg) was without effect in this regard. Those substances that reduced the oxyphenbutazone-induced cortical lesion also ameliorated the focal degenerative change in the lower nephron attributed to this drug. Oral administration of 2:4 dinitrophenol (20 mg/kg) led to only minor cortical tubular necrosis in a few animals.