〔Abstract〕 Objective To investigate the expression level and clinical significance of SAMHD1 protein in esophageal squamous cell carcinoma tissue. Methods Immunohistochemically staining was used to detect SAMHD1 protein expression in 204 cases of esophageal squamous cell carcinoma tissues. Then we analyzed the relationship between it and the gender, age, clinic pathological characteristics of patients with esophageal squamous cell carcinoma and the five-year survival prognosis of patients. Results SAMHD1 was mainly expressed in the cytoplasm or nucleus of esophageal squamous cell carcinoma cells. The positive rate of SAMHD1 expression was not correlated with the patient′s age, gender, tumor T, N, TNM stage, and upper mediastinal lymph node metastasis. However, in large tumors, the low expression of SAMHD1 was more significant(P=0.013). The poorer the degree of tumor differentiation, the lower the expression of SAMHD1(P=0.001). The expression of SAMHD1 was lower in cases of esophageal cancer with abdominal lymph node metastasis(P=0.044). Compared with the high expression SAMHD1 group, the low expression SAMHD1 group had lower cumulative survival(rate) and disease-free survival(rate)(P<0.05). Conclusion SAMHD1 is lowly expressed in esophageal squamous cell carcinoma, the lower the expression level, the worse the prognosis survival.