Endometrioid adenocarcinoma (EAC) of the uterus can show varying patterns of invasion, 1 of which, "MELF," is characterized by the presence of microcystic, elongated, and fragmented glands. However, at present, little is known of the functional alterations in neoplastic cells that are associated with the different patterns of myometrial invasion, including those in MELF. Galectin-3 is a widely distributed and multifunctional carbohydrate binding protein that has been shown to influence many aspects of tumor development and progression, but there are limited and conflicting data regarding galectin-3 expression in EAC. In this study, galectin-3 immunoreactivity was investigated in 22 EACs with specific comparison of staining in the "conventional" endometrioid-type tumor glands and in areas exhibiting MELF pattern invasion. Cytoplasmic galectin-3 was present in all tumors although <50% of cells were stained in approximately one-third of the cases. Nuclear staining was evident in 11 cases, but usually only in a small proportion of cells. The neoplastic epithelium within MELF areas showed a consistent reduction in protein expression, often contrasting with the adjacent galectin-3-positive conventional glands and reactive stromal cells. Conversely, intravascular tumor foci often showed cytoplasmic and nuclear galectin-3 immunoreactivity. The microanatomical variation in galectin-3 expression in EAC suggests that there are localized functional alterations in the neoplastic epithelium and the surrounding stroma during the invasive process. As MELF pattern invasion is associated with the loss of galectin-3 expression, there may be implications for the use of galectin inhibitors in the treatment of endometrial carcinomas and other malignancies.