G protein-coupled receptor 56 (GPR56) belongs to the adhesion G protein-coupled receptor subfamily, which plays a role in cell progression and survival. The aim of this study was to investigate the role of the GPR56 gene in a cell line study and the impact of its protein expression on the prognosis of colorectal cancer (CRC) patients. The effect of GPR56 on tumor cell proliferation (WST-1 assay), invasion (Transwell assay), migration (Transwell assay, wound healing assay), and colony-forming ability (semisolid agar colony-forming assay) was explored. The expression levels of GPR56 in tissue samples of 109 CRC patients were evaluated by immunohistochemistry. The prognostic value of GRP56 was analyzed using univariate and multivariate analyses. The downregulation of GPR56 in the CRC cell line reduced cell proliferation as compared with that in a control sample (48 h; p=0.042, 72 h; p=0.001). Downregulation of the GPR56 expression reduced cell invasion and migration abilities and inhibited colony-forming abilities (p<0.005). The 5-year overall survival rate was worse in the high-expression group as compared with that in the low-expression group (51.6% vs. 74.4%, p=0.008). High GPR56 expression was a significant prognostic factor for overall survival of CRC patients in the univariate (p=0.001) and multivariate (p<0.001) analyses. The expression level of GPR56 plays an important role in tumor progression in CRC, and it may serve as a prognostic indicator in CRC patients.