SH2B1, an adaptor protein associated with obesity, is closely related to the occurrence and development of a variety of tumors. To investigate the clinical significance of SH2B1 in colorectal cancer (CRC), expression of SH2B1 in colorectal normal tissues, adenomas, paracarcinoma tissues, carcinoma tissues, and metastatic tissues from 1003 CRC patients was detected by immunohistochemistry (IHC). The prediction power of SH2B1 for CRC prognosis was evaluated by Kaplan-Meier survival analysis and Cox regression model. Results revealed the expression of SH2B1 in carcinoma tissues was significantly higher than that in other tissues. High expression of SH2B1 was an independent risk factor for both disease-free survival (DFS) and disease-specific survival (DSS) and predicted unfavorable prognosis of CRC as well as poor chemotherapeutic response. Conclusively, SH2B1 can serve as an effective predictor for CRC survival and chemotherapeutic outcomes.