Endometrial intraepithelial neoplasia (also known as 'EIN') is a precursor to endometrioid endometrial adenocarcinoma characterized by monoclonal growth of mutated cells, a distinctive histopathologic appearance, and 45-fold elevated cancer risk. We have applied diagnostic criteria for EIN to 97 successive endometrial biopsies classified as hyperplastic according to World Health Organization criteria and correlated results with computer-assisted morphometry (D-score) and clinical cancer outcomes. Three pathologists separately reviewed all cases for presence or absence of EIN using published criteria (gland area>stromal area, cytologic change in focus of altered architecture, lesion size>1 mm, and exclusion of cancer and mimics). Discordant cases were resolved by a consensus review at a multiheaded scope. Clinical outcomes were obtained in 84 patients from patient visit and pathology records. Diagnoses of presence or absence of EIN were unanimous among all three pathologists in 75% of cases, and intraobserver-reproducibility was very good (kappa 0.73-0.90). Cases rediagnosed as EIN encompassed hyperplasias previously diagnosed as atypical (n=18) or nonatypical (eight complex, two simple). Eight follow-up cancers were scattered between hyperplasia types (5/21 atypical, 3/63 nonatypical), but all classified as EIN (8/25) and D-score <or=1 (8/38). Subjective application of criteria for diagnosis of EIN correlates well with objective morphometry and successfully segregates patients into high and low cancer risk subgroups with better reproducibility than atypical hyperplasia diagnosis.