A barrier to nonsurgical management of premalignant endometrial disease is the need to perform hysterectomy to exclude concurrent myoinvasive endometrioid adenocarcinoma. Occult adenocarcinoma rates for premalignant disease diagnosed by biopsy or curettage are approximately 40%. We applied the histomorphometric 4-class rule ("4C," which measures epithelial abundance, thickness, and nuclear variation) to diagnostic biopsies to predict myoinvasive cancer outcomes at hysterectomy. Women with endometrial biopsies or curettages having a community diagnosis of atypical endometrial hyperplasia were enrolled in a clinical trial in which subsequent hysterectomy was scored for endometrial adenocarcinoma, and 4C rule ability to predict cancer outcomes was measured. Qualifying biopsies were stratified into high- and low-risk histomorphometric subgroups. Two-hundred thirty-three women had biopsies suited to morphometry and scorable hysterectomy outcomes, of which 46% contained adenocarcinoma. Assignment to a high-risk category by the 4C rule was highly sensitive in predicting any (71%) or deeply (92%) myoinvasive adenocarcinoma at hysterectomy, and assignment to a low-risk group had a high negative predictive value for absence of any (90%) or deeply (99%) myoinvasive disease. Volume percentage epithelium was associated with myoinvasive cancer outcomes above a threshold of 50% (P < .001), and a measure of nuclear pleomorphism was significantly increased (P = .004) in deeply myoinvasive cancers. Formal histomorphometry of endometrial biopsies using the 4C rule has been validated as a means to identify a subset of women with premalignant disease who are unlikely to have concurrent myoinvasive adenocarcinoma and who may qualify for alternative nonsurgical therapies.