Background: Pancreatic cancer microenvironment is crucial in cancer development, and cancer-stromal interactions have been recognized as important targets for cancer therapy. Nuclear factor of activated T-cells (NFAT) has been found in T cells as a transcriptional activator of IL-2, and known to be involved in various processes including the immune system. In cancer tissues, NFAT has been reported to be involved in metastasis. In breast and colorectal cancers, NFATc2 and NFAT5 have been reported to interact with integrins to promote cancer cell migration. On the other hand, in pancreatic cancer, NFAT5 has been reported to be a poor prognostic factor via regulation of PGK1 transcription. In the present study, we evaluated the expression of NFATc2 and NFAT5 in pancreatic cancer and examined their relationship with prognosis. Methods: One hundred and sixty five pancreatic cancer patients who underwent curative-intrent resection at our hospital between 2010 and 2020 were included in this study. We performed immunostaining for NFATc2 and NFAT5 using the tissue micro array. We evaluated the expression of NFATc2 and NFAT5 protein and examined their correlation with clinicopathological factors. Results: Of the 165 pancreatic cancer cases, we detected increased NFATc2 protein expression in cytoplasm of cancer cells in 53 cases (32.1%) and NFAT5 in 104 cases (63.0%), and NFATc2/NFAT5 co-expression in 43 cases (26.1%). NFATc2 expression was not correlated with any clinicopathological factors, NFAT5 expression was correlated with venous invasion (p = 0.047), and NFATc2/NFAT5 co-expression was slightly correlated with Stage (p = 0.054). Relapse free survival (RFS) was estimated in all 165 patients. There was no significant difference for RFS in either NFATc2-high group or NFAT5-high group (p = 0.314 or p = 0.574), however, NFATc2/NFAT5 co-expression group showed significantly poor RFS (p = 0.023). Overall survival (OS) was also estimated in all 165 patients. There was no significant difference for OS in either NFATc2-high group or NFAT5-high group (p = 0.146 or p = 0.529), however, NFATc2/NFAT5 co-expression group showed significantly poor survival (p = 0.006). In multivariate analysis, lymphatic invasion, curability and NFATc2/NFAT5 co-expression were independent prognostic factors for RFS, and lymphatic invasion, curability, presence of adjuvant therapy and NFATc2/NFAT5 co-expression were independent prognostic factors for OS. Conclusions: In pancreatic cancer, NFATc2/NFAT5 co-expression was suggested to be involved in the critical process of pancreatic cancer progression, and may be a novel therapeutic target.