Upregulation of mouse double minute 4 (MDM4) is a frequent event in human hepatocellular carcinoma (HCC) but the underlying molecular mechanisms are poorly characterized. In this study a potential role of the phosphoinositide-3-kinase/v-AKT murine thymoma viral oncogene homolog/mammalian target of rapamycin (PI3K/AKT/mTOR) cascade was investigated in the regulation of MDM4 in HCC. Inhibition of the PI3K-AKT and/or mTOR pathways lowered MDM4 protein levels in HCC cells. Mechanistic protection from proteasomal degradation resulted from de-ubiquitination by ubiquitin-specific protease 2a and AKT-mediated phosphorylation of MDM4, thus increasing MDM4 protein levels. These findings were corroborated in a chimeric AKT mouse model. Upregulation of PI3K/AKT/mTOR signaling may result from overexpression of the eukaryotic elongation factor 1A2 (EEF1A2). Finally, a strong association between the expression of EEF1A2, phosphorylated AKT and MDM4 was observed in human HCC samples. Strong activation of the EEF1A2/PI3K/AKT/mTOR/MDM4 signaling pathway was observed in HCC patients with short survival suggesting that targeting this axis might be a promising approach in a subset of HCC patients.