Hydatidiform moles result from abnormal fertilization and have been divided into partial and complete forms based on morphologic, cytogenetic, and clinical features. Little is known about their pathogenesis or malignant transformation. We applied an immunohistochemical marker for the p53 tumor suppressor gene product to placentas with hydropic change and hydatidiform moles to determine whether abnormal p53 gene product accumulation occurs in molar gestations. Ploidy of these placentas was determined by flow cytometry and fluorescence in situ hybridization. The mean percentages of p53-positive cells was determined by counting 200 cytotrophoblastic and proliferating trophoblastic cells. The staining intensity was graded on a scale of 1+ (faint) to 3+ (strong). The mean percentage of p53-positive cells for the placentas were as follows: 8.9% +/- 10.5 for hydropic change; 28.0% +/- 13.2 for partial mole; and 41.0% +/- 19.6 for complete mole. There was a significant difference in p53 expression between hydropic change and partial mole (P = 0.05) and hydropic change and complete mole (P = 0.0008). Although there was a difference between partial mole and complete mole, this did not reach statistical significance (P = 0.15). Hydatidiform moles exhibited 2+ to 3+ staining intensity, whereas hydropic placentas exhibited weaker intensity (1-2+). The finding of p53 gene product overaccumulation in partial and complete moles suggests that p53 gene mutations or alternatively, post-transcriptional changes in the p53 gene product occur resulting in inactivation and stabilization of the protein. This may play a role in uncontrolled trophoblastic proliferation and neoplastic transformation.