Eighty-eight endometrial specimens from 36 postmenopausal breast cancer patients treated with tamoxifen were investigated cytogenetically and molecularly using fluorescence in situ hybridization with appropriate probes for the HMGIC and HMGIY genes. Twenty control specimens, 10 endometrial polyps, and 10 endometrial biopsy specimens were investigated in the same way. Of the 88 specimens, 44 were from endometrial polyps; 3 were from endocervical polyps; 7 were from cystic endometrium; 30 were from normal or atrophic endometrium, normal endocervix, or myometrium; and 4 were from endometrial carcinomas. Chromosome investigation of the endometrial polyps showed the nature of the chromosome changes in tamoxifen-induced polyps to be the same as that in the controls and in sporadic endometrial polyps described in the literature. HMGIC and HMGIY gene rearrangements in both groups were identical as shown by fluorescence in situ hybridization, which also allowed for the detection of seven hidden paracentric inversions involving 12q15, one of which occurred in a cystic endometrium. The carcinomas did not exhibit any of these changes. Because abnormal expression of HMGIC or HMGIY as a consequence of structural chromosome changes in 12q15 or 6p21, respectively, is invariably associated with benign neoplasia, tamoxifen-associated endometrial polyps are unlikely to undergo further malignant transformation, and a mode of action of tamoxifen as an external carcinogen is unlikely.