Lead is an environmental toxicant of great concern for humans and animals. Lead-induced liver damage and malfunction are partly due to a disturbance of the cellular antioxidant balance. Paraoxonase 1 (PON1) and PON2 are highly expressed in the liver and have been proposed as antioxidative enzymes. In this study, the effects of lead on PON1 and PON2 activities were investigated in human hepatoma HepG2 cells by exposing the cells to various concentrations of lead acetate for 24, 48, or 72 h. The results show that a significant increase in reactive oxygen species was observed even at the lowest concentration of lead treatment. However, only the highest concentration of lead significantly influenced cell viability. Lead had no influence on cell-associated PON1 activity, but it significantly decreased cytoplasmic PON2 activity in a concentration- and time-dependent manner. This reduction was rescued by the addition of calcium. A significant increase of PON2 transcript was observed by real-time polymerase chain reaction, while PON2 protein expression did not change in the western blot analysis. Taken together, these results indicate that lead reduces PON2, but not PON1, activity and that this reduction is reversed by calcium. Lead-induced oxidative stress and decreased PON2 activity lead to the upregulation of PON2 transcript. Copyright © 2012 John Wiley & Sons, Ltd.