The KiSS-1 gene has been reported to play an important role as a metastasis suppressor gene in various human malignancies. However, there is little information about its possible role in hepatocellular carcinoma (HCC). In this study, we evaluated the prognostic significance of the expression of KiSS-1 and its receptor AXOR12 in 142 HCC tissue specimens by immunohistochemistry. By using a cutoff level of 50%, immunoreactivity of KiSS-1 and AXOR12 was found in 6 (4%) and 11 (8%) HCCs. The expression of KiSS-1 and AXOR12 in HCC correlated with each other (r = 0.42, p < 0.0001) and with the expression in corresponding, surrounding liver tissue (both r = 0.35, p < 0.0001). Positive AXOR12 immunoreactivity in HCC correlated with advanced pT-stage of tumors and low tumor grading (r = 0.18, p = 0.032; r = -0.18, p = 0.029). High KiSS-1 expression in HCC had a statistically significant influence on diminished disease-free and overall survival in uni- (p = 0.006 and p = 0.002) and multivariate analysis (r = 2.874, p = 0.027 and r = 2.913, p = 0.026). In this study, we report for the first time that elevated KiSS-1 expression level in HCC correlates with worsened clinical outcome, as an independent prognostic marker for the aggressiveness of HCC.