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Background & Objective: Arsenic trioxide (As(2)O(3)) is a new drug used to treat solid tumors. However, the mechanism is still unclear. This study was to investigate the effects of As(2)O(3) on the proliferation of human hepatocellular carcinoma (HCC) cell line SMMC-7721, and to explore the mechanisms., Methods: When treated with 0-8 micromol/L As(2)O(3) for 96 h, the survival rate of SMMC-7721 cells was determined by WST-8 assay. When treated with 2 micromol/L As(2)O(3) for 72 h, the expression of P27(kip1) and c-Jun activation domain-binding protein 1 (JAB1) in SMMC-7721 cells were detected at different time points by Western blot, the subcellular localization of P27(kip1) and JAB1 was detected by subcellular fractionation and immunofluorescent staining., Results: As(2)O(3) significantly inhibited the proliferation of SMMC-7721 cells. The 50% inhibition concentration (IC50) of As(2)O(3) to SMMC-7721 cells was (1.81+/-0.41) micromol/L at 96 h. When SMMC-7721 cells were treated with 2 mumol/L As(2)O(3) for 12 h, the expression of JAB1 was down-regulated and that of P27kip1 was up-regulated. Furthermore, P27(kip1) and JAB1 proteins were translocated from the cytoplasm into nuclei when cells were exposed to 2 micromol/L As(2)O(3) for 12 h and 24 h, respectively. The nuclear accumulation of both proteins was also observed under fluorescence microscope after treatment of 2 micromol/L As(2)O(3)., Conclusion: As(2)O(3) attenuates JAB1 expression, thereby disturbs the location and expression of P27(kip1), and may participate in regulating the proliferation of SMMC-7721 cells through interfering with the function of P27(kip1).