Induction of apoptosis by low concentrations of ethanol in HepG2 cells represents a different mechanism of action from that observed with high ethanol concentrations. The latter is associated with changes in mitochondrial membrane permeability via cytochrome c release. As we previously demonstrated, ethanol at low concentrations triggers the Fas-apoptotic pathway characterized by trimerization of the Fas-receptor, with subsequent activation of the Fas associated death domain protein and caspase-8. Inhibition of caspase-8 completely prevents ethanol-induced apoptosis, indicating the important regulatory effect of caspase-8 in this process. However, the interrelation of the Fas-apoptotic pathway and other signaling pathways remains unknown. Therefore, the aim of the present study was to evaluate the effect of low concentrations of ethanol on other signal transduction pathways. For this, HepG2 cells were treated with 1 mM ethanol for 10 min and the phosphorylation state of various signaling kinases was determined. The relationship between ethanol-induced apoptosis and other signaling pathways was analyzed in pre-treated cells with specific inhibitors and subsequent ethanol exposure for 24 h. We found that ethanol at low concentrations activates the Ras signaling pathway and such activation is associated with an increase in apoptosis. In contrast, the MAPK signaling cascade had an antiapoptotic effect. In conclusion, our results demonstrate a regulatory effect of signal transduction pathways other than the Fas-pathway on apoptosis induced by millimolar concentrations of ethanol in HepG2.