One of the major side effects of cisplatin is nephrotoxicity, leading to acute renal failure. Recent study has suggested a role of hydroxyl radicals and p53 in renal cell injury by cisplatin. This study determined the possible involvement of oxidative stress in p53 activation. In rat mesangial cells, cisplatin treatment induced apoptosis and p53 activation. Pifithrin-$alpha$, a pharmacological inhibitor of p53, suppressed cisplatin-induced apoptosis. Cisplatin also induced reactive oxidative species (ROS) generation. Of interest, cisplatin-induced apoptosis was prevented by N-acetyl-cysteine (NAC), a general antioxidant. NAC diminished p53 activation during cisplatin treatment. Puerariae Radix and Rehmanniae Radix Preparata with antioxidative activity were reduced the cisplatin-induced ROS generation, caspase-3 activity and p53 activation. In conclusion, ROS may contribute to p53 activation to initiate cisplatin-induced apoptosis in rat mesangial cells. In result, antioxidative effect of Puerariae Radix and Rehmanniae Radix Preparata prevented cisplatin-induced apoptosis through inhibition of p53 activation.