BACKGROUND Serpin peptidase inhibitor, clade A member 3 (SERPINA3) belongs to the serpin family with an inhibitory activity against proteases. Its aberrant expression has been observed in a wide range of tumor cells. However, its clinical significance and biological function in endometrial cancer have been rarely studied. We designed a study to determine the levels of SERPINA3 and its significance in patients with endometrial cancer. AIM To investigate the clinical significance and role of SERPINA3 expression in endometrial cancer cells. METHODS Eighty endometrial tissue samples collected from patients with endometrial cancer were included in an observation group and 80 paraffin-embedded tissues samples collected from patients with normal endometrial tissues undergoing myomectomy were employed as a control group between January 2014 and December 2018. The expression of SERPINA3 mRNA was detected by quantitative polymerase chain reaction (PCR) for all endometrial tissues included in the study. RESULTS The positive expression rate of SERPINA3 protein in endometrial cancer cells was 71.25% in the observation group, which was significantly higher than that in the control group (31.25%; P < 0.05). There was no correlation between SERPINA3 protein in endometrial cancer cells and the age range at which women experienced menopause ( P > 0.05). However, it was associated with pathological grade, clinical stage, vascular invasion, and lymph node metastasis ( P < 0.05). Pathological grade, clinical stage, vascular invasion, and lymph node metastasis were independent prognostic factors for endometrial cancer. CONCLUSION The follow-up study of SERPINA3 can be used as a prognostic biomarker for endometrial cancer and as one of the targets for bio-targeted therapy for endometrial cancer.