The aim of this study was to evaluate HDPR1 expression in esophageal squamous cell carcinoma (ESCC) and the relationship between HDPR1 and beta-catenin by immunohistochemical analysis. The clinical relevance of these proteins was also analyzed. Immunohistochemistry was performed on paraffin-embedded tissue specimens from 184 ESCC patients to detect the expression of HDPR1 and beta-catenin. The correlation between the results of immunoexpression and the clinicopathologic features was processed statistically. Increased cytoplasmic and nuclear HDPR1 expression was noted in 100 (54.3%) and 131 (71.2%) of 184 specimens, respectively. Statistical analysis showed significant associations of cytoplasmic HDPR1 with regional lymph node metastasis (p = 0.021) and P-stage (p = 0.004). The increased nuclear staining was only correlated with P-stage (p = 0.047). Significant associations of coexpression of cytoplasmic and nuclear HDPR1 with regional lymph node metastasis (p = 0.015) or P-stage (p = 0.002) were observed. Enhanced cytoplasmic expression of HDPR1 was positively correlated with increased cytoplasmic but not reduced membranous beta-catenin expression (r = 0.239, p = 0.027 and r = 0.126, p = 0.089, respectively). These finding suggested that cytoplasmic HDPR1 protein expression was associated with tumor malignant progression via beta-catenin accumulation. It implicated that cytoplasmic HDPR1 expression may serve as a potential predictive factor for lymph node metastasis and tumor development in ESCC.