Purpose <p>Very often endometrioid endometrial carcinoma (EEC) arises in the setting of endometrial hyperplasia (EH). The area of endometrial neoplastic precursor lesions and their progression into cancer phenotypes mediated by Akt/mTOR pathway are under reported. In the present study, we determined the immunohistochemical expression of proteins (Akt, mTOR, and eIF-4E) of this pathway in EH along with EEC to assess the role of Akt/mTOR pathway in the initial stage of endometrial carcinogenesis. This may aid the development of additional potent molecular therapies at its earliest stages.</p> Methods <p>It was a prospective observational case–control study included biopsies of normal proliferative endometrium (<i>n</i> = 23), EH with and without atypia (<i>n</i> = 39), and EEC (<i>n</i> = 40). Biopsies were collected in 10% neutral formalin for routine histology and immunohistochemistry of pAKT, pMTOR, and eIF-4E. Statistical analysis was performed using version 22.0 SPSS software, and to assess association, Chi-square test was carried out.</p> Results <p>A total of 102 endometrial biopsies were assessed. Age ranged from 30 to 70&#xa0;years. Positive immunoexpression of pAkt, pMTOR, and eIF-4E was observed in 65%, 63%, 93% of EEC cases, respectively, and 80%, 70%, 100% of EH with atypia cases.</p> Conclusion <p>Upregulation of pAKT, pMTOR, and eIF-4E was observed in EH with atypia along with EEC cases suggesting that activation of Akt/mTOR pathway might be the initial step in endometrial carcinogenesis. A better understanding of the molecular process of this pathway may aid in the development of additional potent molecular therapies at its earliest stages.</p>