Background and the purpose of the study: Peroxisome proliferator ligands have been found to have a hepatoprotective effect against induced injuries in hepatotoxicants. FeIII:8HQ induces oxidative stress in freshly isolated cells. The hepatoprotective effects of clofibrate and its novel siliconized analog (silafibrate) against the FeIII:8HQ complex are compared here for the first time. Methods: A siliconized analog of clofibrate synthesized by replacement of the chlorine atom in the phenoxy ring with trimethylsilyland ethyl2-methyl-2-(4- (trimethylsilyl)phenoxy)propionate was prepared. Hepatocytes were obtained from male rats by a two-step collagenase perfusion. The viability of isolated hepatocytes was evaluated by Trypan blue exclusion method. Levels of reactive oxygen species (ROS) were measured with the fluorescent probes2′,7′-dichlorofluorescein diacetate (DCFHDA). Mitochondrial membrane potential was measured by using Rhodamine 123 fluorescence. Results: Incubation of hepatocytes with low to moderately toxic doses of silafibrate (200, 250, 400, and 500 μM) for 3 hours did not evoke a notable toxic response in three time-repeated experiments. However, higher doses (1, 2mM) have significant toxicity in Trypan blue exclusion cell viability experiments. Mitochondrial membrane potential decrease was prevented by pretreatment of hepatocytes with clofibrate and/or silafibrate, 20 minutes before adding FeIII:8HQ complexes (I, II). 100 μM clofibrate protected hepatocytes against FeIII: 8HQ induced ROS production, whereas silafibrate with 100, 200, and 400 μM strongly inhibited ROS production. Conclusion: These results demonstrate that fibrates have an in vitro hepatoprotective effect against oxidative stress. Silafibrate, the novel analog, has a better effect in protection against oxidative stress in comparison with clofibrate.