Oxygen metabolites play an important role in the pathogenesis of myoglobinuric acute renal failure (ARF). Previously, we have reported a down regulation of peroxisome proliferator activated receptor gamma (PPARgamma) in glycerol-induced ARF, and the induction of PPARgamma has been shown to provide renal protection. In this study, we determined the protective influence of U74389G, a hydroxyl radical scavenger in myoglobinuric ARF, and its association with PPARgamma-mediated renal protection in the rat. Vascular responses to AII were determined in renal pre-glomerular vessels following the induction of ARF with glycerol (50%, v/v, i.m.). The extent of renal damage and function were assessed with or without pre-treatment with U74389G (10 mg/kg x 21 days). In ARF, AII vasoconstriction was enhanced (97%; p < 0.05), and AII production was doubled. U74389G reduced AII vasoconstriction and production by 42% (p < 0.05) and 40% (p < 0.05), respectively. U74389G reduced proteinuria (85%; p < 0.05), which was four times higher in ARF. Similarly, U74389G enhanced Na+ excretion twofold while reducing plasma creatinine (24%; p < 0.05) and BUN (31%; p < 0.05). U74389G attenuated free radical generation in ARF while nitrite excretion was unchanged. In renal pre-glomerular vessel, PPARgamma expression, activity, and mRNA were significantly lower in ARF rats; this was unchanged with U74389G treatment. On the other hand, U74389G significantly reduced NFkappaB protein expression, which was elevated in ARF by 25% (p < 0.05). We suggest that antioxidant U74389G blunted renal injury and improved renal function in glycerol-induced ARF through the reduction of free radical production and/or inhibition of NFkappaB without affecting PPARgamma.