Objective: To investigate the expression and clinical value of neurotrophin receptor-interacting melanoma antigen-encoding protein (NRAGE) in small hepatocellular carcinoma (HCC) and its clinical significance. Methods: The NRAGE expressions in 160 specimens of small HCC tissue with paired adjacent non-tumorous tissue were determined by immunohistochemical staining. The relations of NRAGE expression with clinicopathological features and prognosis of small HCC patients were analyzed. Results: The positive expression rate of NRAGE in small HCC tissue was significantly higher than that in adjacent tissues (63.13% vs. 14.38%, P<0.05). NRAGE expression was significantly related to age, preoperative AFP level, complete capsule and recurrence (all P<0.05). Univariate prognostic analysis showed that microvascular invasion, AFP level, childhood lesions, complete capsule, recurrence, serosal invasion, Barcelona stage, degree of differentiation and NRAGE expression were factors affecting the prognosis of small HCC patients (all P<0.05), and multivariate prognostic analysis showed that NRAGE expression together with microvascular invasion, preoperative AFP level, recurrence, and Barcelona stage were independent risk factors for prognosis of small HCC patients (all P<0.05). In addition, the 5-year survival rate of patients with high NRAGE expression was significantly lower than those with low NRAGE expression (35.63% vs. 54.23%, P<0.05). Conclusion: NRAGE expression is up-regulated in small HCC tissue, and patients with high NRAGE expression may have an unfavorable prognosis.