BACKGROUND Recent studies in our laboratory have demonstrated that lead is cytotoxic to human liver carcinoma (HepG2) cells, showing a 48 h-LD50 of 35.5 ± 9.2ug/mL. However, its molecular mechanisms of toxicity are still largely unknown. Hence, the aim of the present study was to use HepG2 cells as a test model to investigate the molecular mechanisms of lead-induced oxidative stress and modulation of cellular response proteins. METHODS To achieve this goal, we performed lipid peroxidation assay for malondialdehyde (MDA) determination, western blot and densitometric analyses for genes and related proteins expression in human liver carcinoma cells. RESULTS Data obtained from the lipid peroxidation assay demonstrated a significant increase (p ≤ 0.05) of MDA levels in lead-treated HepG2 cells compared to control cells. Western Blot analysis showed a strong dose-response relationship with regard to p53 expression, and a significant repression in cyclin A in lead-treated cells. CONCLUSIONS Findings from this research indicate that lead is able to cause oxidative stress, cell cycle arrest through activation of the 53-kDa tumor suppressor protein and down regulation of the cyclin A protein in human liver carcinoma (HepG2) cells.