Mucinous adenocarcinoma is an uncommon type of endometrial adenocarcinoma for which precursor lesions have yet to be clarified. During a review of noncancerous endometrial lesions in postmenopausal women, we found that mucinous endometrial glands showed variable degrees of epithelial changes that ranged from the formation of simple tubular glands to the formation of complex glands with papillary tufts, and some of the glands with papillary tufts were architecturally similar to low-grade mucinous adenocarcinomas. Based on histological similarities, we have postulated that mucinous metaplasia could be a precursor lesion of mucinous adenocarcinoma. To explain the pathogenetic significance of endometrial mucinous metaplasia, we analyzed the immunohistochemical expression of ER, PR, MKI67, PTEN, β-catenin, P16(INK4A), TP53, and PAX2 in 21 endometrial mucinous metaplasias, screened for KRAS (n=16) and PTEN (n=14) mutations, and compared expression patterns between samples with simple mucinous glands, those with complex glands having intraglandular papillary tufts, and endometrioid adenocarcinomas. Compared with the surrounding flat mucinous epithelium and simple mucinous metaplasia, the intraglandular papillary tufts associated with papillary mucinous metaplasia were characterized by selectively decreased expression of PAX2 (P=0.029) and PR (P<0.001), and overexpression of P16(INK4A) (P=0.014). There were no significant differences in the levels of expression of ER, PTEN, β-catenin, TP53, and MKI67 between the two groups. In contrast with endometrioid adenocarcinomas, rates of MKI67 proliferation were very low in both groups. Mutations in KRAS were identified in 89% of cases with papillary mucinous metaplasia, in contrast to 14% in simple mucinous metaplasia (P=0.001). No PTEN mutations were observed in either of the two groups. In conclusions, immunohistochemical and molecular genetic profiling suggest that papillary mucinous metaplasia is a possible precancerous lesion in a subset of endometrial carcinomas.