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Both inhibitor of growth 4 (ING4) and phosphatase and tensin homolog deleted on chromosome 10 (PTEN) are well known as tumor suppressors that are closely related to tumor occurrence and progression. It was reported that ING4 and PTEN showed synergistic antitumor activities in nasopharyngeal carcinoma cells. The two tumor suppressors demonstrated synergistic effect on growth inhibition and apoptosis activation. In this study, we investigated their therapeutic potential in hepatocellular carcinoma (HCC) cells. Recombinant adenoviruses co-expressing ING4 and PTEN (Ad-ING4-PTEN) were constructed, and the antitumor effect on SMMC-7721 and HepG2 HCC cells was evaluated. Ad-ING4-PTEN cooperatively inhibited cell growth, stimulated apoptosis, and suppressed invasion in both HCC cells, and regulated cell cycle in SMMC-7721. Further studies showed that the combination of ING4 and PTEN by Ad-ING4-PTEN cooperatively enhanced the alteration of the expression of cell cycle-related proteins (p53, p21, and cyclin D1) and apoptotic factors (Bad, Bcl-2, Bcl-XL, and Bax), which are involved in the regulation of cell cycle and the activation of apoptotic pathways, leading to the synergistic antitumor effect. These results indicate that the combination of ING4 and PTEN may provide an effective therapeutic strategy for HCC.