Hepatocellular carcinoma (HCC) is one of the most difficult cancer disease for diagnosis and treatment, with a low survival rate and high recurrence rate and mortality. Nuclear factor of activated T-cells 5 (NFAT5) is mediated by osmolality and proved to be a carcinogenic gene in some tumor. However in our study we considered NFAT5 as tumor suppressor of HCC. RT-qPCR was performed for NFAT5 expression in tumor tissues. NaCl was applied to make hyperosmotic treatment. We knockdowned and overexpressed NFAT5 to investigate its role in HCC. FCM was used for apoptosis assay. Transwell and scratch assay is proceeded for invasion.NFAT5 is downregulated in HCC tissue and cell lines, besides, upregulated by hyperosmolality. NFAT5 promotes apoptosis by regulating PARP-1,BAX/BCL2 while inhibits invasion through EMT-related protein claudin-1 and fibronectin. Hyperosmolality is also a protective factor for HCC. We considered hyperosmolality exhibited his protective effect by inducing NFAT5.In a word, NFAT5 inhibits invasion and promotes apoptosis in HCC, associated with osmolality.