Endometrial carcinoma is one of the most common malignancies of the female genital tract, and there is an urgent need for discovery of novel factor for prognostic assessment and therapeutic targets to endometrial carcinoma. Herein, 2-DE and MALDI-Q-TOF MS/MS-based proteomic approach was used to identify differentially expressed proteins in endometrial carcinoma. Of the 99 proteins identified, cyclophilin A was one of the most significantly altered proteins and its over-expression was confirmed using RT-PCR and Western blot analyses. Immunohistochemistry suggested a link between cyclophilin A expression and poor differentiation and decreased survival (P<0.01). Knockdown of cyclophilin A expression by RNA interference led to the significant suppression of the cell growth and the induction of apoptosis in endometrial carcinoma HEC-1-B cells in vitro (P<0.01), and the inhibition of tumor growth in vivo (P<0.01). These data suggest that cyclophilin A may serve as a novel prognostic factor and possibly an attractive therapeutic target for endometrial carcinoma.