Endometrial curettings from 204 patients containing severe forms of atypical hyperplasia, carcinoma in situ, and well-differentiated carcinoma were compared with subsequent hysterectomy specimens to evaluate and identify the most useful histologic criteria for predicting the presence of invasive carcinoma. Endometrial stromal invasion, increased degrees of nuclear atypism, mitotic activity, cellular stratification, and epithelial necrosis in curettings were associated with a greater likelihood of carcinoma in the uterus. Of these, stromal invasion was the most significant feature. When stromal invasion was absent, carcinoma was present in the uterus in only 17%, and the carcinomas were well differentiated and confined to the endometrium or only superficially invasive. When stromal invasion was present in curettings, residual carcinoma was present in the uterus in half, and of these, one third were moderately or poorly undifferentiated and a quarter invaded deeply into the myometrium. The criteria for invasion are 1) an irregular infiltration of glands associated with an altered fibroblastic stroma or desmoplastic response; 2) a confluent glandular pattern in which individual glands are uninterrupted by stroma and merge to form a cribriform pattern of stromal replacement; 3) an extensive papillary pattern; and 4) replacement of stroma by masses of squamous epithelium. To qualify as invasion, 2, 3, and 4 must occupy at least one half (2.1 mm) of low power field 4.2 mm in diameter. Because of the important role of stromal invasion in predicting prognosis, future classifications of endometrial neoplasia should utilize this feature in distinguishing atypical hyperplasia from well differentiated adenocarcinoma.