Signal transducer and activator of transcription 1 (STAT1) regulates cell proliferation and survival. The present study aimed to investigate the role of STAT1 in the development and progression of human hepatocellular carcinoma (HCC). The levels of STAT1 expression in 36 HCC and 12 non-HCC liver tissues were examined by immunohistochemistry. The effect of STAT1 overexpression or silencing on the proliferation and apoptosis of HCC cells was determined by MTT and flow cytometric assays. The effect of STAT1 overexpression or silencing on the levels of p53 and cyclin E expression was determined by quantitative PCR and western blot assays. The level of STAT1 expression in the HCC tissues was significantly lower compared to the level in the non-HCC liver tissues and was negatively associated with the histological grade of HCC and serum HBsAg, anti-HCV and α-fetoprotein positivity in HCC patients. Induction of STAT1 overexpression significantly inhibited HepG2 cell proliferation and enhanced HCC cell apoptosis, accompanied by upregulation of p53 expression and STAT1 phosphorylation, but a reduction in cyclin E expression in HepG2 cells. In contrast, knockdown of STAT1 by introduction of STAT1-specific siRNA promoted HepG2 cell proliferation, but inhibited HCC cell apoptosis, accompanied by significant downregulation of p53 expression, but enhancement of cyclin E expression in vitro. Our data suggest that STAT1 may inhibit HCC growth by regulating p53-related cell cycling and apoptosis.