Amplification of 1q21 has been detected in 58% to 78% of primary hepatocellular carcinoma cases, suggesting that one or more oncogenes within the amplicon play a critical role in the development of this disease. The chromodomain helicase/adenosine triphosphatase DNA binding protein 1–like gene (CHD1L) is a recently identified oncogene localized at 1q21. Our previous studies have demonstrated that CHD1L has strong tumorigenic ability and confers high susceptibility to spontaneous tumors in a CHD1L‐transgenic mouse model. In this study, we demonstrate that the antiapoptotic ability of CHD1L is associated with its interaction with Nur77, a critical member of a p53‐independent apoptotic pathway. As the first cellular protein identified to bind Nur77, CHD1L is able to inhibit the nucleus‐to‐mitochondria translocation of Nur77, which is the key step of Nur77‐mediated apoptosis, resulting in the hindrance of the release of cytochrome c and the initiation of apoptosis. Knock‐down of CHD1L expression by RNA interference could rescue the mitochondrial targeting of Nur77 and the subsequent apoptosis. Further studies found that the C‐terminal Macro domain of CHD1L is responsible for the interaction with Nur77, and a CHD1L mutant lacking residues 600‐897 failed to interact with Nur77 and prevented Nur77‐mediated apoptosis. More importantly, we found that the inhibition of Nur77‐mediated apoptosis by endogenous CHD1L is a critical biological cellular process in hepatocarcinogenesis. Conclusion: We demonstrate in this study that overexpression of CHD1L could sustain tumor cell survival by preventing Nur77‐mediated apoptosis. (HEPATOLOGY 2009.)