AF1q impairs survival in hematologic and solid malignancies. AF1q expression is associated with tumor progression, migration, and chemoresistance, and acts as a transcriptional co-activator in WNT and STAT signaling. This study evaluates the role of AF1q in patients with resectable esophageal cancer (EC). A total of 278 patients operated on for esophageal cancer were retrospectively included, and the expression of AF1q, CD44, and pYSTAT3 was analyzed following immunostaining. Quantified data were processed to correlational and survival analysis. In EC patients, an elevated expression of AF1q was associated with CD44 (p = 0.004), and pYSTAT3 (p = 0.0002). High AF1q expression in primary tumors showed high AF1q expression in the corresponding lymph nodes (p= 0.016). AF1q expression was higher after neoadjuvant therapy (p= 0.0002). Patients with AF1q-positive EC relapsed and died earlier compared to patients with AF1q-negative EC (disease-free survival (DFS), p= 0.0005; disease-specific survival (DSS), p= 0.003); in the multivariable Cox regression model, AF1q proved to be an independent prognostic marker (DFS, p= 0.01; DSS, p= 0.03). AF1q is associated with WNT and STAT signaling; it impairs and independently predicts DFS and DSS in patients with resectable EC. The testing of AF1q could facilitate prognosis estimation and provide a possibility of identifying the patients responsive to the therapeutic blockade of its oncogenic downstream targets.