Synthetically produced perfluorinated chemicals (PFCs) are widely used in industrial products because of their anti-wetting and surfactant properties. PFCs are suspected carcinogens and a possible mechanism of action is generation of oxidative stress. We have investigated the potential of five different PFCs to generate reactive oxygen species (ROS) and to induce oxidative DNA damage in HepG2 cells. Perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) increased the intracellular ROS production by 1.52-fold (95% CI, 1.37–1.67) and 1.25-fold (95% CI, 1.10–1.40), respectively. However, the increase in ROS production was not concentration-dependent and the compounds did not generate DNA damage that could be detected by the alkaline comet assay as strand breakage and alkali-labile sites or formamidopyrimidine-DNA-glycosylase (FPG) sites. Perfluorobutane sulfonate (PFBS) and perfluorohexanoic acid (PFHxA) did not generate ROS or DNA damage. Only the exposure to perfluorononanoic acid (PFNA) caused a modest increase in DNA damage at a cytotoxic concentration level, which was detected as lactate dehydrogenase (LDH) release into the cell medium. This was not related to ROS generation. Collectively, these results indicate that PFCs induce only modest effects in terms of ROS production and DNA damage in a cell line representing the human liver.