Objective: To investigate the expression and clinical significance of sphingosine-1-phosphate transporter 2 (spinster homolog 2, SPNS2) in colorectal cancer. Methods: Colorectal cancer and adjacent normal tissues were collected from 133 patients undergoing colorectal cancer resection in Anhui Provincial Hospital from January 2010 to June 2013. The expression of SPNS2 protein was detected by immunohistochemistry. RT-qPCR was performed on the cancer tissues and adjacent normal tissues of 29 patients with colorectal cancer from February 2018 to June 2018. The relationship between the expression of SPNS2 in cancer tissues and clinicopathological features of colorectal cancer patients was analyzed using χ2test. The relationship between the expression of SPNS2 and prognosis of patients with colorectal cancer was analyzed based on univariate and multivariate analysis. Results: Immunohistochemistry results indicated that the expression of SPNS2 in colorectal cancer tissues was higher than that in adjacent normal tissues (81.20% vs. 22.60%, χ2=69.136, P<0.001). The results of RT-qPCR indicated that the expression of SPNS2 mRNA in colorectal cancer tissues was significantly higher than that in the corresponding adjacent normal tissues (t=3.974, P<0.001). The overexpression of SPNS2 protein was closely related to tumor differentiation, lymph node metastasis (pN), tumor size, and depth of invasion (Tx); this difference was statistically significant (P<0.001). The survival time of patients with negative SPNS2 expression was significantly longer than that of patients with positive expression (χ2=13.080, P<0.001). Univariate and Cox multivariate analyses showed that abnormal expression of SPNS2 affects the overall survival of colorectal cancer patients and is an independent influencing factor for patient prognosis. Conclusions: The positive expression of SPNS2 in colorectal cancer is related to the occurrence and development of colorectal cancer. SPNS2 can be used as a new colorectal tumor marker to evaluate the prognosis of patients, monitor the invasion and metastasis of postoperative tumors, and serve as a new target for diagnosis and treatment.