The aim of this study was to assess the antigenotoxic activity of several garlic organosulfur compounds (OSC) in the human hepatoma cell line HepG2, using comet assay. The OSC selected were allicin (DADSO), diallyl sulfide (DAS), diallyl disulfide (DADS), S-allyl cysteine (SAC) and allyl mercaptan (AM). To explore their potential mechanisms of action, two approaches were performed: (i) a pre-treatment protocol which allowed study of the possible modulation of drug metabolism enzymes by OSC before treatment of the cells with the genotoxic agent; (ii) a co-treatment protocol by which the ability of OSC to scavenge direct-acting compounds was assessed. Preliminary studies showed that, over the concentration range tested (5-100 microM), the studied OSC neither affected cell viability nor induced DNA damage by themselves. In the pre-treatment protocol, aflatoxin B1 genotoxicity was significantly reduced by all the OSC tested except AM. DADS was the most efficient OSC in reducing benzo(a)pyrene genotoxicity. SAC and AM significantly decreased DNA breaks in HepG2 cells treated with dimethylnitrosamine. Additionally, all the OSC studied were shown to decrease the genotoxicity of the direct-acting compounds, hydrogen peroxide and methyl methanesulfonate. This study demonstrated that garlic OSC displayed antigenotoxic activity in human metabolically competent cells.