Objective: To investigate the expression and clinical significance of p27 and Cyclin-E in endometriosis (EMS). Methods: A total of 100 patients with ovarian EMS confirmed by surgery and pathology in Mianyang Third People’s Hospital from April 2018 to April 2021 were selected as an observation group to collect endometrial ectopic lesions. In addition, 100 patients with uterine fibroids undergoing hysterectomy at the same time were selected as a control group. The normal endometrial tissues were collected and the expressions of p27 and Cyclin-E in the 2 groups were examined by immunohistochemistry. Results: The positive rate of Cyclin-E in the observation group (86.00%) was significantly higher than that in the control group (11.00%) (P<0.05). The positive rate of p27 in the observation group (57.00%) was significantly lower than that in the control group (78.00%) (P<0.05). The expression of p27 and Cyclin-E was related to the degree of growth, cyst size, and dysmenorrhea (P<0.05). p27 and Cyclin-E were negatively correlated in EMS (P<0.05). Conclusion: The changes in p27 and Cyclin-E levels play an important role in the occurrence and development of EMS.