The cell surface adhesion receptor CD44 reportedly affects the development and progression of cancers. Moreover, CD44 gene rs187115 polymorphism appears to be genetic determinant of cancer susceptibility. We investigated whether CD44 rs187115 polymorphism is associated with colorectal cancer (CRC) risk and prognosis. We enrolled 669 CRC cases and 826 controls in this three-center case-control study in a Chinese Han population. All individuals were genotyped by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Cross-over analysis, multivariate logistic regression, Kaplan-Meier method, and Cox regression analysis were used for analysis. In this study, CD44 rs187115 polymorphism was associated with increased risk for CRC. Stratified analyses revealed that CD44 rs187115 polymorphism was correlated with increased risk for CRC in females, drinkers, smokers, and those aged ≥ 60 years. In addition, rs187115 polymorphism was significantly associated with TNM III+IV stage, lymph node metastasis and tumor size in CRC patients. Combined effects of CD44 rs187115 polymorphism (GG/AG vs. AA) and environmental factors (smoking and drinking) further increased the risk of CRC. GG genotype carriers showed poorer overall survival than AA genotype carriers. Cox regression analysis showed that drinking, CD44 rs187115 polymorphism, and TNM stage were independent prognostic factors affecting CRC. These findings show that CD44 rs187115 polymorphism may be a potential biomarker predictive of CRC susceptibility and prognosis.