Objective: To investigate the expression of high-mobility group box 2 (HMGB2) in colorectal cancer tissue and its clinical significance. 
Methods: The surgical specimens and clinical data of 82 patients with colorectal cancer treated from January 2012 to January 2014 in the Department of Gastrointestinal Surgery of Maoming People’s Hospital were collected. The HMGB2 expressions in the specimens were detected by immunohistochemical staining. The relations of HMGB2 expression with the clinicopathologic factors and postoperative tumor-free and overall survival rates were analyzed, and the risk factors for postoperative tumor-free and overall survival rates of colorectal cancer patients were also analyzed. 
Results: The proportion of cases with high HMGB2 expression was 60.9% (50/82) and with low HMGB2 expression was 39.1% (32/82). The high HMGB2 expression was significantly related to histological differentiation, clinical stage, T classification, N classification and M classification of the colorectal cancer patients (all P<0.05). Both 5-year tumor-free survival and overall survival rates in patients with high HMGB2 expression were significantly lower than those in patients with low HMGB2 expression (27.7% vs. 38.7%, P<0.05; 32.1% vs. 41.5%, P<0.05). The results of multivariate analyses showed that both HMGB2 expression and M classification were independent risk factors for tumor-free survival (HR=1.771, 95% CI=1.146–4.923, P=0.027; HR=3.874, 95% CI=1.886–7.824, P=0.002) and overall survival rates (HR=1.823, 95% CI=1.035–3.198, P=0.005; HR=3.865, 95% CI=1.770–8.278, P=0.001) in patients with colorectal cancer. 
Conclusion: High HMGB2 expression is closely associated with malignant clinicopathologic features in patients with colorectal cancer, and also is an independent risk factor for poor prognosis in patients with colorectal cancer.