['To detect the expression levels of ubiquitin-specific protease 22 (USP22) in human esophageal squamous cell carcinoma (ESCC) and to correlate it with clinicopathologic and prognostic data.', 'The immunoreactivity of USP22 protein was analyzed in 157 pathologically characterized ESCC tissues by immunohistochemistry. All statistical analyses were performed with SPSS statistical software to evaluate the association of USP22 protein with clinicopathologic factors and survival.', 'High expression of USP22 protein was detected in 50.96 % of 157 ESCC tissues and significantly associated with invasion depth, lymph node metastasis, pathologic stage and tumor relapse (P < 0.05, respectively). Univariate survival analysis showed that patients with high expression of USP22 protein had a significantly poorer 5-year disease-specific survival (P = 0.002), and multivariate survival analysis showed that high expression of USP22 protein was an independent prognosticator for unfavorable disease-specific survival (P = 0.039). Further survival analysis stratified by pathologic stage demonstrated that high expression of USP22 protein significantly predicted unfavorable clinical outcome (P = 0.029) among patients with pathologic stage II(b)-III diseases.'] Is uSP22 nuclear expression significantly associated with progression and unfavorable clinical outcome in human esophageal squamous cell carcinoma?