Single nucleotide polymorphism (SNP) in some genes is a candidate for having or developing a cancer. Cathepsin B (CTSB) is considered to be the biomarker of cancers. The study aimed to evaluate the impacts of three SNPs in CTSB gene on the risk and progress of hepatocellular carcinoma (HCC). The SNPs of CTSB C76G (rs12338), CTSB A4383C (rs13332), and CTSB A8422G (rs8898) from 135 patients with HCC and 520 control participants in Taiwan were determined by real-time PCR. Through analyzing by statistics, we found that the polymorphism of rs13332 was significantly associated to the risk of HCC cancer; a significantly high frequent tumor size development was observed in HCC patients carrying rs12338 polymorphic genotype than those carrying ancestral genotype. The SNPs of rs12338, rs13332, and rs8898 were irrelevant to the frequencies of HCC clinical status and the levels of HCC clinicopathological markers. In conclusions, CTSB A4383C SNP is observed modestly more often in patients who developed HCC than in healthy controls and might be associated with the risk of HCC. The association between CTSB C76G SNP and greater tumor size may warrant further study in regards to the biology of HCC.