Differentiating uterine serous carcinoma (USC) from endometrioid adenocarcinoma (EAC) could be problematic, especially in high-grade EACs and tumors exhibiting architectural variations. To address this issue, we evaluated 103 endometrial carcinoma cases using 4 immunomarkers, beta-catenin, IMP3, PTEN, and p53. Cases included 31 USCs, 57 EACs, and 15 mixed EAC-USCs. Of 31 USCs and 57 EACs, 8 and 9, respectively, were considered diagnostically difficult and challenging. beta-catenin was more frequently expressed in EAC (P = .001); p53, PTEN, and IMP3 were more frequently found in USC (P < .001 for each). IMP3 was the best independent predictive marker for USCs. The best marker combination for predicting USCs was PTEN+/IMP3+ (exact odds ratio, 163.87; 95% confidence interval, 19.62 to infinity; P < .001). IMP3 was consistently negative in all 9 challenging EAC cases and consistently positive in all 8 challenging USC cases. None of the markers or their combinations demonstrated any value in making the diagnosis of serous component in mixed EAC-USC tumors. IMP3 immunoexpression and the IMP3+/PTEN+ pattern are the best independent and combination markers, respectively, to predict USCs. We strongly recommend using them in difficult and challenging cases.