Abstract: Chronic exposure to coplanar polychlorinated biphenyls (PCBs), a potent inducer of toxic reactive oxygen species (ROS), in the environment and food can cause liver diseases. It remains unknown whether caffeic acid derivatives (CADs) exerted protective effect on PCB-induced hepatotoxicity. We sought to evaluate the activities of 3 CADs on PCB169-induced oxidative stress and DNA damage in the liver. Male ICR mice were administered with 1 mmol/mL PCB169 at 5 mL/kg body weight for 2 weeks. The mice were given CADs by gastric gavage for 3 weeks. We found that PCB169 decreased the growth rate and reduced the levels of superoxide dismutase (SOD), glutathione (GSH) and GSH peroxidase (GPx). It increased the liver weight, malondialdehyde (MDA) and 8-hydroxy-29-deoxyguanosine (8-OHdG) levels and CYP1A1 activity in the liver tissues and plasma of mice (P<0.05). Pretreatment of mice with CADs restored the above parameters to normal levels. There was a synergistic protective effect between CADs in preventing MDA and 8-OHdG formation and inducing CYP1A1 and phase II metabolism enzyme (SOD, GPx) activities (P<0.05). In conclusion, PCB169 induced hepatotoxicity and pretreatment with CADs had synergistic protective effects on liver damage.