The prognostic value of aromatase, cyclooxygenase 2 (COX-2), HER-2/neu, and p53 expression was determined in endometrioid endometrial cancer. Tissue microarrays were constructed comprising samples from 315 endometrioid endometrial cancer patients. Expression of aromatase, COX-2, HER-2/neu, and p53 was determined by immunostaining and related to classical clinicohistopathologic parameters, in addition to recurrence of disease and survival. Median follow-up time for all patients was 5.0 years. Patients were classified as Fédération Internationale de Gynécologie Obstétrique stage I (59.0%), stage II (17.1%), stage III (19.4%), and stage IV (4.1%). Sixty-five patients (20.6%) developed recurrent disease, and 38 (12.1%) died because of endometrial cancer. Aromatase, COX-2, HER-2/neu, and p53 expression was observed in 133 (42.2%), 107 (34.0%), 17 (5.4%), and 21 (6.7%) tumor cases, respectively. Aromatase expression in tumor cells was related to aromatase expression in stromal cells (P < 0.0001) and to HER-2/neu expression in tumor cells (P = 0.019). Aromatase expression in tumor as well as stromal cells was related to a low stage of disease (P = 0.02 and P = 0.001, respectively), whereas aromatase expression in stromal cells was also related to a low tumor grade (P = 0.021). P53 expression was related to a high stage and a high grade (P = 0.006 and P < 0.0001, respectively). In multivariate analysis, p53 overexpression was independently related to death because of the disease (P = 0.043; odds ratio 3.0; 95% confidence interval, 1.0-8.7). For COX-2, HER-2/neu, and aromatase, no relation with any other histopathologic parameter or survival was found. In conclusion, aromatase and p53 expression are related to tumor grade and stage of disease, whereas p53 is an independent prognostic factor in endometrioid endometrial cancer.