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ABSTRACT Background FXYD3 is a Na/K‐ATPase modulator which is upregulated in pancreatic ductal adenocarcinoma (PDAC), but its prognostic role is unknown. This study evaluated FXYD3 expression in chemo‐naive patients with surgically‐resected PDAC at a single centre (1993–2014). Method FXYD3 expression was assessed in tumour specimens using immunohistochemistry. Results 145 of 180 PDAC tumour specimens were FXYD3‐immunopositive (80.5%). There was no difference in median overall survival between the FXYD3 negative (27.60 months) and positive groups (25.00 months) (log‐rank p = 0.9718). FXYD3 expression correlated positively with late‐stage disease (OR 3.041, 95% CI 1.190–7.455, p = 0.0175). There was no significant association with T stage, positive lymph nodes, perineural invasion, lymphovascular invasion or histological grade. Conclusion Immunohistochemical FXYD3 expression does not predict survival in chemo‐naive PDAC patients, but is associated with late‐stage disease. The high rate of FXYD3 overexpression warrants therapeutic evaluation.