Polychlorinated biphenyls (PCBs) are ubiquitous and persistent environmental pollutants that accumulated in the food chain. Traditionally they are divided into dioxin-like (DL)- and non-dioxin-like (NDL)-PCBs. NDL-PCBs have been shown to have tumor promotive activity in mice and co-carcinogenic effects in rats. However the mechanisms are poorly understood, hampering the risk assessment of NDL-PCBs. We have previously shown that TCDD attenuates p53 response by phosphorylating its regulator Mdm2 at Ser166, and that Erk can mediate this effect in hepatocytes. In this study we investigated the effects of 20 NDL-PCBs (concentration range 0.01-10microM) on pMdm2 Ser166, pErk Tyr204 and p53 on HepG2 cells. Six of the NDL-PCBs induced pErk Tyr204 and pMdm3 Ser166. This effect correlated with lowered basal levels of p53, as well as with an attenuated p53 response induced by etoposide and leptomycin B. Similar effects were induced by TCDD and the DL-PCB 126. We conclude that both DL-PCBs and NDL-PCBs in low concentrations can induce alterations in p53 signaling and that these effects can be correlated to rat liver carcinogenesis.