Subcutaneous injection of sodium arsenite (NaAs, 12.5 mg/kg) into BALB/c [wild-type (WT)] mice causes acute renal dysfunction characterized by severe hemorrhages, acute tubular necrosis, and cast formation, with increases in serum blood urea nitrogen and creatinine levels. Concomitant enhancement in intrarenal interferon (IFN)-γ expression prompted us to examine its roles in this pathology. IFN-γ-deficient (IFN-γ^−/−) mice exhibited higher serum blood urea nitrogen and creatinine levels and exaggerated histopathological changes, compared with WT mice. Eventually, IFN-γ^−/− mice exhibited a high mortality (87.5%) within 24 hours after NaAs challenge, whereas most WT mice survived. The intrarenal arsenic concentration was significantly higher in IFN-γ^−/− mice later than 10 hours after NaAs treatment, with attenuated intrarenal expression of multidrug resistance-associated protein (MRP) 1, a main transporter for NaAs efflux, compared with WT mice. NF-E2-related factor (Nrf) 2 protein, a transcription factor crucial for MRP1 gene expression, was similarly increased in the kidneys of both strains of mice after NaAs treatment. In contrast, the absence of IFN-γ augmented transforming growth factor-β-Smad3 signal pathway and eventually enhanced the expression of activating transcription factor 3, which is presumed to repress Nrf2-mediated MRP1 gene expression. Thus, IFN-γ can protect against NaAs-induced acute renal injury, probably by maintaining Nrf2-mediated intrarenal MRP1 gene expression.