Colorectal cancer (CRC) is the third most common form of cancer and the second leading cause of cancer-related death in the Western countries. In order to detect common CRC genetic variants, genome-wide association studies (GWAS) have been performed and reported some novel CRC susceptibility variants. RHPN2 is located on 9q13.11, which encodes a member of the rhophilin family of Ras-homologous (Rho)-GTPase binding proteins. RHPN2 gene rs10411210 polymorphism was identified to be significantly associated with CRC in European ancestry. GWAS and candidate studies investigate whether rs10411210 polymorphism is associated with CRC risk in European, Asian and American populations. However, most studies reported no association. Evidence shows that RHPN2 rs10411210 variant may be a prognostic biomarker for patients with surgically resected CRC. Here we reevaluated this association using large-scale samples from 15 studies (131580 samples including 53564 CRC cases and 78016 controls) using meta-analysis method by searching the PubMed and Google Scholar databases. We did not identify significant heterogeneity among these 15 studies (P=0.4201 and I²=2.8%). Our results showed significant association between rs10411210 and CRC (P=9.17E-14, odds ratio (OR)=1.10, 95% confidence interval (CI) 1.07–1.13). In subgroup analysis, we found significant association between rs10411210 and CRC in European population with P=5.70E-09, OR=1.14, 95% CI 1.10-1.20 and Asian population with P=3.36E-07, OR=1.11, 95% CI 1.07–1.16, but not American population with P=0.0576, OR=1.05, 95% CI 1.00–1.09. Collectively, our analysis further highlights significant association between rs10411210 polymorphism and colorectal cancer.