Erythrodiol (EO) is a pentacyclic triterpenic alcohol found in the leaf of olive tree and in the olive oil. In this study, we evaluate the nature of cytotoxicity of EO on HepG2 hepatocarcinoma human cells studying the changes induced on cell viability, reactive oxygen species (ROS) production, antioxidant defence systems and proteome. The results obtained reveal that EO markedly decrease HepG2 cell viability without change ROS levels. A significant reduction in the glutathione and NADPH concentrations are produced with selective changes in the activity of antioxidant enzymes (glutathione peroxidase, glutathione reductase, glucose 6-phosphate dehydrogenase and 6-phosphogluconate dehydrogenase). Proteomics data reveals that 41 and 3 proteins are decreased completely or partially in abundance, respectively; and 29 are completely increased. The functional enrichment analysis showed that an impairment of important metabolic processes and in the nuclear transport of mature mRNA is produced while the biosynthesis of AMP and cell cycle G2/M phase transition are induced. The transcription factors and miRNA implied in this response are also identified