Despite previously reported high hepatic safety profile of ibuprofen (IBP), but other reports oppose its use in hepatic patients. The aim of this study is to evaluate the possible effect of IBP besides its oxime (OI) and ketone (KI) derivatives in both normal liver and in acute CCl4-induced hepatotoxicity. Sixty adult male Wistar rats were used, divided into 8 groups. Group 1: received saline water as normal control. Groups 2,3,4: treated with IBP, OI or KI respectively. Group 5: treated with CCl4 to induce hepatotoxicity. Groups 6,7,8: treated with IBP, OI or KI respectively 30 minutes before CCl4 administration. Current results showed that despite the apparent hepatotoxic effects of IBP, which were less evident in OI and KI, on normal liver that may be explained by possible immunological idiosyncrasy, they ameliorated both hepatocellular and cholestatic damage induced by CCl4, which may be attributed to their anti-inflammatory and anti-oxidant potential. OI and KI derivatives, rather than IBP, showed higher hepatic safety profile and stronger hepatoprotective potential against acute CCl4-induced hepatotoxicity, which favor their use, instead of IBP, in concurrent hepatic diseases.