Both serous intraepithelial carcinoma and endometrial glandular dysplasia are associated with uterine serous carcinoma. Recently a candidate serous cancer precursor containing p53 mutations (p53 signature) was described in the fallopian tube. We analyzed normal and neoplastic endometrium for a similar entity. In total 10 endometrial polyps involved by intraepithelial and/or invasive carcinoma and 137 benign polyps were studied. All were stained for p53 and MIB-1. A subset of p53 signatures and carcinomas were analyzed for gamma-H2AX and p53 mutations. p53 signatures were identified in 7 of 10 cases intraepithelial carcinoma and were multicentric in 2. In one case, the signature was in continuity with intraepithelial carcinoma. Of 137 benign polyps (4%), 6 contained p53 signatures. The MIB-1 fraction in most signatures was less than 5%, and ranged from 50 to 90% in carcinomas. DNA damage (gamma-H2AX) was demonstrated in both p53 signatures and adjacent carcinomas but not in benign polyps. Shared identical p53 mutations were found in paired signatures and carcinomas in two of three cases analyzed, including one case with multiple signatures. In one, a coexistent invasive serous cancer was not found to contain a p53 mutation. In a third, a p53 signature and an invasive cancer harbored two different p53 mutations. This is the first description of p53 signatures adjacent to carcinoma, suggesting a role for this entity in the genesis of serous malignancy. The significance of p53 signatures in benign conditions (polyps) remains to be determined. The role of the p53 signature in early serous neoplasia is discussed.