This study was performed to investigate the role of DNA cytometry in the evaluation of molar and nonmolar pregnancies. DNA ploidy analysis was performed on paraffin-embedded tissue from 53 molar (35 complete, 18 partial) and 24 nonmolar (13 hydropic, 11 nonhydropic) conceptuses. Nuclear suspensions were analyzed by both flow and image cytometry and there was excellent correlation (96%) in the classification of DNA diploid, triploid, and tetraploid cases using these two methods. DNA ploidy analysis revealed a high proportion of tetraploid nonmolar conceptuses (42%) and complete moles (47%). The majority of partial moles were triploid (89%). Tissue sections from all cases were also studied by image cytometry to identify the cellular subpopulations (decidua, villous stromal cells, inner trophoblast, and extravillous trophoblast) with abnormal DNA content. In the triploid cases, all of the villous cell subtypes had an abnormal DNA content consistent with the development of partial moles from a triploid conceptus. In contrast, the majority of tetraploid cases showed high proliferative activity of the extravillous trophoblast whereas the other villous cell subtypes were diploid. These results suggest that tetraploid complete moles may arise from a diploid conceptus with the development of tetraploidy related to polyploidization of the hyperplastic extravillous trophoblast. Tissue section image cytometric DNA analysis can aid in our interpretation of ploidy results and our understanding of the biology of molar pregnancies.