The detection of foam cells in cervicovaginal smears obtained from post-menopausal women suggests the possibility of an endometrial lesion. Ultrastructural studies have suggested that foam cells represent endometrial stromal cells but the histogenesis of these cells has not been firmly established. To investigate the origin and diagnostic significance of foam cells, we analyzed the morphology and immunophenotype of these cells in endometrial tissue specimens and correlated the findings with cervical smears obtained within the preceding 6 months. Selected biopsies containing foam cells were evaluated using four well-characterized macrophage markers: KP-1(CD68), HAM 56, MAC 387, and lysozyme. Foam cells were found in 11 (38%) of 29 simple hyperplasias, 7 (50%) of 14 complex hyperplasias, 6 (50%) of 12 complex atypical hyperplasias, 21 (70%) of 30 adenocarcinomas, 1 (4%) of 25 samples with stromal breakdown, and 0 of 30 specimens showing normal cycling endometrium. Foam cells were also found in smears preceding the histologie diagnosis of 2 (13%) simple hyperplasias, 2 (25%) complex hyperplasias, 3 (43%) complex atypical hyperplasias, 5 (28%) adenocarcinomas, 5 (28%) cases of stromal breakdown, and 0 of 8 normal tissue specimens examined. Foam cells were immunoreactive with at least 2 of the 3 macrophage-specific antibodies in all 21 biopsies studied. Our results suggest that foam cells phenotypically represent macrophages and not endometrial stromal cells. Foam cells are identified in a significant percentage of cervical smears and endometrial tissue specimens obtained from women with endometrial pathology. The morphology and immunophenotype of foam cells, however, does not appear to be useful in distinguishing benign endometrial stromal breakdown, endometrial hyperplasia, and endometrial adenocarcinoma.