Detailed histopathologic examination remains to be the basis for the diagnosis of hydatidiform mole (HM). However, poor sampling, necrosis, and earlier uterine evacuation can lead to uncertainty in the diagnosis. Also, the criteria are subjective, resulting in considerable interobserver variability. The p57(KIP2) gene is paternally imprinted and maternally expressed, and the presence of its protein product serves as a surrogate marker for the nuclear maternal genome. Because a complete HM (CHM) is the only type of conceptus lacking a maternal contribution, p57(KIP2) immunostaining is correspondingly absent, whereas it is present in CHM mimics. Although analysis of DNA microsatellite polymorphisms is a reliable method for the diagnosis and classification of HM, it is not universally available. To assess the relative accuracy of p57(KIP2) immunostaining and molecular diagnosis by nuclear DNA microsatellite polymorphisms in discriminating CHM from its mimics, we analyzed archival tissue from 33 case patients (7 with a definitive diagnosis of CHM, 16 with a possible diagnosis of HM, and 10 with normal placentas) by both methods. Concordant results were obtained in all cases, and p57(KIP2) immunostaining accurately identified all cases of CHM from the groups with a definitive or possible diagnosis of HM. p57(KIP2) immunohistochemistry is a time- and cost-effective means of distinguishing CHM from its mimics in challenging cases.