Endometrial intraepithelial carcinoma (EIC) is a recently described lesion characterized by replacement of endometrial surface epithelium or glands by malignant cells resembling high-grade invasive endometrial carcinoma. EIC has been identified in a high proportion of uteri containing serous carcinoma, but its association with other endometrial tumors is unknown. To determine the strength and specificity of the association of EIC with tumors displaying serous differentiation, the appearance of the endometrium in 38 uteri with serous carcinoma, 113 with endometrioid carcinoma, and 34 with malignant mixed mesodermal tumor (MMMT) were compared. EIC was present in 34 (98%) uteri with serous carcinoma compared with 7 (6%) uteri removed for endometrioid carcinoma (P = .0001). Hyperplasia without atypia was found in only 2 (5%) of 38 serous carcinomas compared with 38 (34%) of 113 endometrioid carcinomas. Similarly, atypical hyperplasia was not found in any uterus with serous carcinoma, but was present in 14 (12%) uteri with endometrioid carcinoma (P = .02). The endometrium was inactive or atrophic in 29 (76%) patients with serous carcinoma compared with 33 (29%) with endometrioid carcinoma (P = .0001). EIC was found in five (56%) of nine MMMTs with a serous epithelial component (serous-MMMT) compared with one (4%) of 25 MMMTs woth an endometrioid epithelial component (endometrioid-MMMT). As with endometrioid and serous carcinomas, hyperplasia with and without atypia was more common with endometrioid-MMMTs as compared with serous-MMMTs. Hyperplasia was found in 25 (100%) and atypical hyperplasia in 8 (32%) of 25 endometrioid-MMMTs, but in none of the nine serous-MMMTs. This study shows that EIC is frequently and specifically associated with uterine tumors displaying serous differentiation. The findings suggest that EIC represents a form of intraepithelial tumor growth characteristic of serous carcinoma and serous MMMT and that EIC is the likely precursor of these neoplasms. In addition, the findings provide further evidence supporting the view that MMMTs represent variants of carcinoma not sarcoma.