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Background: The aim of the study was to investigate the relationship between urokinase-type plasminogen activator (uPA) and mitogen-activated protein kinase 38 (p38MAPK), and preliminarily analyze their relationship with clinical characteristics of esophageal cancer. Materials and methods: Immunohistochemistry and Western blot were used to detect the expressions of uPA and p38MAPK in patients with esophageal cancer. The relationship between them and clinicopathological features was analyzed by chi-squared test and Spearman correlation. Prognosis was performed using Kaplan–Meier and Cox proportional hazard models analysis. Results: The expressions of uPA and p38MAPK proteins were significantly higher in esophageal squamous cell carcinoma or adenocarcinoma than in normal esophageal mucosa tissue (both P<0.0001). The expression of uPA was significantly correlated with the depth of invasion of esophageal cancer (P=0.0067), tumor size (P=0.0364), and pathological stage (P<0.0001); p38MAPK expression vs esophageal cancer tissue type (P=0.0043), esophageal cancer infiltration depth (P=0.0097), tumor size (P=0.0015), and pathological stage (P<0.0001). Both were not significantly associated with lymph node staging, gender, age, and esophageal cancer histological type. There was a positive correlation between uPA and p38MAPK expressions (r=0.7301, P=0.0104). Kaplan–Meier analysis showed that the overall survival time of patients with positive expression of uPA or p38MAPK protein was significantly shorter, and the time of recurrence or metastasis of esophageal cancer was significantly earlier in patients with uPA-positive expression. Multivariate analysis of Cox model showed that uPA, p38MAPK, and pathological staging were independent factors influencing survival. Conclusion: The expressions of uPA and p38MAPK may play an important role in the progression of esophageal cancer, and there is a close relationship between the two proteins, which may be one of the prognostic indicators. [ABSTRACT FROM AUTHOR]