BACKGROUND AND STUDY AIM: We aim to study the immunohistochemical expression of both hypoxia-inducible factor-1α (HIF-1α) and mammalian target of rapamycin (mTOR) in endometriosis to provide new evidence for a targeted endometriosis therapy. PATIENTS AND METHODS: This study comprised 106 endometriotic cases diagnosed clinically and histopathologically. The immunohistochemical method was done to determine the expression of HIF-1α and mTOR. RESULTS: Endometriotic glands showed significant cytoplasmic expression of both markers in patients with poor ovulation, severe endometriosis, and infertile for >2 years ( P <0.001). Also, patients with intense and worst pain show significant immunohistochemical expression of both markers ( P <0.001). There is a significant correlation between mTOR and HIF-1α expression in endometriotic tissue samples as P <0.001. CONCLUSIONS: Our data suggest that both mTOR and its downstream target HIF-1α transcription factor are both disrupted in patients with endometriosis, which is consistent with aberrant activation of these pathways and their possible contribution to the pathogenesis of endometriosis. These results could offer a promising novel opportunity to be blocked therapeutically. As new management options need to be refined in particular in severe cases and infertile patients with endometriosis, therefore future studies are warranted to investigate treating endometriosis with mTOR inhibitors; the latter are already in clinical trials in phase III and IV, treating solid tumors as well as non-neoplastic disorders.