Malignant cells are characterized by abnormalities of the cytoskeleton, and actin filaments in particular show marked disturbances of this normally well-organized network. Of the many actin-binding proteins, gelsolin plays a particularly important role in the remodeling of the actin cytoskeleton. Gelsolin expression is lost in transformed cells and in carcinomas of the breast and bladder, suggesting a role for gelsolin as a tumor suppressor. Because other human cancers have not yet been studied, we analyzed carcinomas of the endometrium and ovary for changes in gelsolin expression. Normal endometrial glands were positive in the secretory phase, whereas proliferative glands had lost expression. Although both simple and complex endometrial hyperplasias without atypia expressed gelsolin, some complex hyperplasias with atypia lost gelsolin expression. Expression in endometrial adenocarcinomas was related to grade; 11 of 14 grade II and III tumors were negative compared with 0 of 2 grade I tumors. However, grade I foci within the grade II and III tumors retained gelsolin expression, as did areas exhibiting squamous differentiation, regardless of the grade of the glandular component. Normal ovarian surface epithelium and all 4 ovarian cystadenomas expressed gelsolin, whereas 13 of 13 serous and mucinous carcinomas were negative. In contrast, 3 of 4 ovarian clear cell carcinomas were positive. The loss of gelsolin expression in ovarian and endometrial carcinomas is consistent with a tumor suppressor function for gelsolin, although its absence in proliferative glands and expression in squamous differentiation suggests a more complex relation than that previously reported for other tumors. Further investigation is needed to establish whether or not gelsolin expression provides diagnostic or prognostic information.