Objective To explore the relationships among Paired box 8 （PAX8）， α-enolase （ENO1）， human epididymal protein 4 （HE4）， and neuropilin-2 （NRP-2）， as well as their associations with the severity of endometrial cancer and their value in predicting the prognosis of patients. Methods From January 2021 to November 2022， 168 patients diagnosed with endometrial cancer were recruited， all of whom underwent surgical treatment. Following the surgical intervention， a follow-up protocol was initiated， requiring patients to attend follow-up appointments every three months. The follow-up period extended until November 2025. During this period， 3 patients were lost to follow-up. Ultimately， 165 patients with endometrial cancer were included in the study， forming the endometrial cancer group， with a median follow-up duration of 48 months. Among these patients， 35 cases with a poor prognosis （poor prognosis was defined as any occurrence of distant metastasis， patient death， or recurrence of endometrial cancer） were classified as the poor prognosis group， while the remaining 130 cases were designated as the good prognosis group. Concurrently， 165 patients with benign endometrial diseases were selected as the benign endometrial diseases group， and 165 healthy women were recruited as the healthy control group. Clinical data and serum levels of PAX8， ENO1， HE4， and NRP-2 were compared across the groups. The serum levels of PAX8， ENO1， HE4， and NRP-2 in relation to different pathological features were analyzed. The relationship between the serum levels of PAX8， ENO1， HE4， and NRP-2 and the severity of endometrial cancer was examined using Spearman correlation analysis. By designating patients with a poor prognosis as positive cases and those with a good prognosis as negative cases， the predictive value of the serum levels of PAX8， ENO1， HE4， and NRP-2 for the prognosis of patients with endometrial cancer was evaluated using the receiver's operating characteristics （ROC） curve. Results The serum levels of PAX8， ENO1， HE4， and NRP-2 in the endometrial cancer group were significantly higher than those in the benign endometrial disease group and the healthy control group. Additionally， the levels in the benign endometrial disease group were significantly higher than those in the healthy control group （P < 0.05）. In patients， the levels of serum PAX8， ENO1， HE4， and NRP-2 in those with FIGO stage Ⅲ-Ⅳ， poor differentiation， myometrial infiltration ≥ 1/2， and lymph node metastasis were significantly higher than those in patients with FIGO stage Ⅰ-Ⅱ， medium-high differentiation， myometrial infiltration < 1/2， and no lymph node metastasis （P < 0.05）. The serum levels of PAX8， ENO1， HE4， and NRP-2 were positively correlated with FIGO stage， myometrial infiltration， and lymph node metastasis， while negatively correlated with differentiation （P < 0.05）. The serum levels of PAX8， ENO1， HE4， and NRP-2 in patients with a poor prognosis were significantly higher than those in patients with a good prognosis （P < 0.05）. The combined detection of the serum levels of PAX8， ENO1， HE4， and NRP-2 could predict the area under the curve （AUC） of endometrial cancer patients， and this AUC value was higher than that of individual detection （P < 0.05）. Conclusions Serum levels of PAX8， ENO1， HE4， and NRP-2 are abnormally expressed in patients with endometrial cancer. This abnormal expression is closely related to the severity of the disease. Moreover， the combined examination of these markers has high clinical value in predicting the prognosis of patients with endometrial cancer.