Objective To investigate the association between the methylation levels of plasma cyclin E1 （CCNE1）， iroquois homeobox protein 2 （IRX2）， and xenotropic and polytropic retrovirus receptor 1 （XPR1） genes， and the clinicopathological features and prognosis in patients with endometrial cancer （EC）. Methods A total of 120 patients with EC who underwent surgical treatment at the hospital between June 2018 and December 2022 （study group） were selected and divided into the survival group （88 cases） and the death group （32 cases） based on the patients' prognosis. Another 100 healthy volunteers of matching age were recruited as the control group. The methylation levels of plasma CCNE1， IRX2， and XPR1 genes were detected using methylation-specific real-time quantitative polymerase chain reaction. The relationship between the methylation levels of plasma CCNE1， IRX2， and XPR1 and the prognosis of EC patients was analyzed by the Kaplan-Meier method. The Cox risk regression model was employed to analyze the prognostic factors of EC patients. Receiver operating characteristic （ROC） curves were utilized to evaluate the predictive value of plasma CCNE1， IRX2， and XPR1 methylation for poor prognosis in patients with endometrial cancer. Results Compared with the control group， the methylation levels of plasma CCNE1 and XPR1 in the study group were lower， whereas the methylation level of IRX2 was higher （P < 0.05）. In patients with FIGO stage Ⅲ + Ⅳ， poorly differentiated histological grade， myometrial infiltration depth ≥ 1/2 myometrium， and lymph node metastasis， the methylation levels of CCNE1 and XPR1 were low， while the methylation level of IRX2 was high （P < 0.05）. A total of 120 EC patients were followed up for 5 - 36 months， with a median follow-up time of 21 months. Among them， 32 patients died， and the 3-year overall survival rate was 73.33% （88/120）. The 3-year overall survival rate of patients with low expression of plasma CCNE1 and XPR1 methylations was lower than that of the high-expression groups （χ² = 4.729， 6.136； P = 0.030， 0.013）， and the 3-year overall survival rate of patients with high expression of plasma IRX2 methylation was lower than that of the low-expression groups （χ² = 6.569； P = 0.010）. Compared with the survival group， the methylation levels of CCNE1 and XPR1 in the death group were lower， and the methylation level of IRX2 was higher （P < 0.05）. Hypermethylation of IRX2 was a risk factor for poor prognosis in patients with EC， while hypermethylation of CCNE1 and hypermethylation of XPR1 were protective factors （P < 0.05）. The AUC values for plasma CCNE1， IRX2， and XPR1 methylation as individual predictors of poor prognosis in EC patients were 0.827， 0.820， and 0.816， respectively； The AUC for the combined prediction was 0.941， indicating superior predictive performance （Z = 3.427， 2.610， 3.068； P = 0.001， 0.009， 0.002）. Conclusions Reduced levels of CCNE1 and XPR1 methylation， along with elevated levels of IRX2 methylation， in the plasma of endometrial cancer patients are closely associated with clinical and pathological characteristics as well as poor prognosis. The combination of these three markers holds high predictive value for poor prognosis in endometrial cancer patients.