In the present study, we investigated the expression of ubiquitin-like with PHD and ring finger domains 2 (UHRF2) in colon cancer and adjacent normal tissues and estimated the clinicopathological significance and predictive value of UHRF2 expression in colon cancer. Using quantitative real-time PCR, tissue microarray (TMA), western blot analysis and immunohistochemical staining, we evaluated UHRF2 mRNA and protein levels in tumor tissues and paired adjacent normal epithelium. We found that UHRF2 was upregulated at both the transcriptional and translational levels in tumor tissues. Immunohistochemical detection of UHRF2 on a TMA containing 203 paired specimens showed that increased cytoplasmic UHRF2 was significantly associated with clinical stage, depth of invasion, nodal involvement, tumor histologic grade and the presence of metastasis. Patients with UHRF2-positive tumors had a much lower disease-free survival [hazard ratio (HR) 9.511, P<0.001] and overall survival (HR 9.820, P<0.001). Univariate and multivariate analyses were performed to determine the correlation between these parameters and the clinical and pathological variables of the study population verifying that UHRF2 immunoreactivity emerged as an independent prognostic factor in the multivariate analysis. UHRF2 may contribute to the progression of colon carcinogenesis and function as a novel prognostic indicator after curative operation.