Abstract Background: Periampullary cancer (PC) is a global medical burden, although infrequent but less than 5% of patients experience an overall survival of five years or more. The study aims to analyze the importance of Epidermal Growth Factor Receptor (EGFR)/Insulin-Like Growth Factor 1 Receptor (IGF1R) - Beta-catenin (β-catenin)- CD44 pathway in the development of periampullary cancer of Indian patients. Materials and Methods: Expression profile of EGFR, IGF1R, β-catenin, and CD44 was verified by immunohistochemical analysis in primary tumor samples (N=14) and respective adjacent normal tissues. Results: In periampullary carcinoma patients, a high level of EGFR expression was seen in 64% of the samples along with co-expression of IGF1-R in 77.8% samples. Furthermore, the high expression of EGFR and IGF1R significantly correlated with the increased expression of β-catenin along with CD44 expression of the tumors. Conclusion: The EGFR/IGF1R - β-catenin- CD44 pathway seems to be important in the development of PC with clinical importance. Key-words: Periampullary cancer; EGFR; IGF1R; β-catenin; CD44 Key Messages: Interplay of EGFR, IGF1R, β-Catenin and CD44 expressions is important phenomena in the development of PC. Citation Format: Suvendu Maji, Biswabandhu Bankura, Chinmay Kumar Panda, Neyaz Alam. Activation of EGFR/IGF1R - beta catenin - CD44 pathway in periampullary cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1985.