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Our study mainly investigated ubiquitin-specific protease 4 (USP4) expression in pathogenesis of esophageal cancer. The data showed significantly increased expression of USP4 in cancer tissues compared to that in para-carcinoma tissues (68.38% ± 25.60% vs 13.04% ± 9.95%, P = 0.000) and positive correlation between USP4 and pathology grade (r = 0.249, P = 0.014), although survival analysis revealed that USP4 expression was positively associated with the prognosis (32.4% vs 10.9%, P = 0.043). Grouped analysis revealed that the prognosis of patients with high USP4 expression were significantly better only in the small tumor subgroup (diameter ≤ 5 cm) (52.6% VS 8.6%, P = 0.001) and the early stage subgroup (stages 1 and 2) (60.0% VS 16.7%, P = 0.006). Moreover, in the subgroup of clinical stages 1 and 2 with tumor diameter ≤ 5 cm, high USP4 expression prolonged the survival time of esophageal cancer patients more significantly (75.5% VS 5.9%, P = 0.000). Based on these results, we speculated that it was possible to significantly improve the prognosis of patients with low USP4 expression by targeted therapy in early esophageal cancer. Taken together, our study uncovered a previously unknown function of USP4 in esophageal cancer and more investigations would be carried out to further study its regulation gene network and molecular biological mechanism in esophageal cancer. [ABSTRACT FROM AUTHOR]