Hepatocellular carcinoma (HCC) is the second leading cause of cancer deaths in Taiwan. CD44, one of the well-known tumor markers, plays an essential role in tumor cell differentiation, invasion, and metastasis. We investigated the CD44 single-nucleotide polymorphisms (SNPs) with environmental risk factors related to HCC susceptibility and clinicopathological characteristics. Six SNPs of CD44 were analyzed using a real-time polymerase chain reaction (PCR) in 203 patients with HCC and in 561 cancer-free controls. We determined that the individuals carrying at least one G allele at CD44 rs187115 has higher risk of developing HCC than did wild-type (AA) carriers. We further observed that the CD44 rs187115 polymorphisms with at least one G allele had a higher frequency of distribution in nonsmoking stage III/IV HCC patients, compared with wild-type carriers. Our results suggested that patients with CD44 rs187115 variant genotypes (AG+GG) were associated with a higher risk of HCC development and that these patients might possess chemoresistance, causing more likely progression to late-stage HCC than wild-type carriers without the overexpression of CD44 induced by heavy smoking. CD44 rs187115 might be involved in CD44 isoform expression of p53 stress response in HCC and provide a marker for predicting worst-case prognosis of HCC.