Diclofenac (DCLF), a prominent prescription NSAID, is widely used for the management of arthritis and, as analgesics and antipyretics. In addition, DCLF is also a powerful inducer of oxidative stress and genomic injury, and has limitations on its use due to its nephrotoxic potential [1]. This study was designed to investigate whether DCLF-mediated oxidative stress modulates the expression of pro- and anti-apoptotic genes in mouse kidneys. Female ICR mice (25-35 g), fed ad libitum, were administered a dose of DCLF 200 mg/Kg, po and sacrificed 0, 6, 12, 18 and 24 h later. Study parameters included analysis of serum chemistry (BUN, Creatinine, CK, and ALT), measurement of oxidative stress (MDA, SOD, Total Nitrate+Nitrite) and western-blot analysis of bcl-2, bcl-XL, bad, bax, and p53. DCLF-induced considerable nephrotoxicity (BUN elevation: by 2.8 to 5-fold; creatinine elevation: 1.76 to 2.35 fold) at 0, 6, 12, 18, 24hr and parallel changes were noted in lipid peroxidation, nitric oxide production and genomic DNA fragmentation. The most dramatic changes were observed in western blot analysis, which included (i) Substantial increases in the expression of pro-apoptotic bax and bad proteins (at 12, 18, 24hrs), (ii) reduction in the expression of anti-apoptotic bcl-2 and bcl-xl genes (at 6, 12, 18, 24hrs) and minor changes in p53 was observed. Overall, biochemical changes mirrored the genetic changes. This study clearly established the possible involvement of cell death regulating genes during DCLF-induced nephrotoxicity; however their clinical significance needs to be determined.