BACKGROUND: Cleavage factor Im 25 (CFIm25) affects the prognosis and progression of cancer by regulating alternative polyadenylation; however, its role in colorectal cancer remains unclear. METHODS: A standard EnVision tissue microarray was used to evaluate the expression of CFIm25 by immunohistochemistry in 363 patients with colorectal cancer. The correlation between CFIm25 expression and clinicopathological characteristics was analyzed using the χ2 test. Univariate analysis was used to study the relationship between clinicopathological characteristics and patient prognosis. Multivariate analysis was performed using the Cox regression model to identify independent prognostic factors for patients with colorectal cancer. RESULTS: Statistical analysis revealed that CFIm25 expression was significantly associated with vascular invasion (P=0.000), serous invasion (P=0.007), pT stage (P=0.016), and clinical stage (P=0.007). Age, vascular invasion, nerve invasion, serosal invasion, differentiation, clinical stage, recurrence, and CFIm25 expression were significantly correlated with the survival time of colorectal cancer patients (P<0.05). The mean overall survival rate in colorectal cancer patients with decreased CFIm25 expression was only 88.53 months, compared with 110.69 months in the high expression group (P=0.000). Decreased CFIm25 expression indicated a worse prognosis in patients with colorectal cancer. Further analysis by the Cox multivariate model showed that CFIm25 (HR, 0.543; 95% CI: 0.372-0.792; P=0.002) and serosa invasion (HR, 1.470; 95% CI: 1.032-2.094; P=0.033) are independent prognostic factors for colorectal cancer. CONCLUSIONS: Decreased CFIm25 expression indicates a worse prognosis of colorectal cancer patients and could be a novel target for the treatment of colorectal cancer in the future. KEYWORDS: Polyadenylation; survival analysis; colorectal cancer (CRC); CFIm25.