Distinction of hydatidiform moles from nonmolar specimens (NMs) and subclassification of hydatidiform moles as complete hydatidiform mole (CHM) and partial hydatidiform mole (PHM) are important for clinical practice and investigational studies; however, diagnosis based solely on morphology is affected by interobserver variability. Molecular genotyping can distinguish these entities by discerning androgenetic diploidy, diandric triploidy, and biparental diploidy to diagnose CHMs, PHMs, and NMs, respectively. Eighty genotyped cases (27 CHMs, 27 PHMs, 26 NMs) were selected from a series of 200 potentially molar specimens previously diagnosed using p57 immunohistochemistry and genotyping. Cases were classified by 6 pathologists (3 faculty level gynecologic pathologists and 3 fellows) on the basis of morphology, masked to p57 immunostaining and genotyping results, into 1 of 3 categories (CHM, PHM, or NM) during 2 diagnostic rounds; a third round incorporating p57 immunostaining results was also conducted. Consensus diagnoses (those rendered by 2 of 3 pathologists in each group) were also determined. Performance of experienced gynecologic pathologists versus fellow pathologists was compared, using genotyping results as the gold standard. Correct classification of CHMs ranged from 59% to 100%; there were no statistically significant differences in performance of faculty versus fellows in any round (P-values of 0.13, 0.67, and 0.54 for rounds 1 to 3, respectively). Correct classification of PHMs ranged from 26% to 93%, with statistically significantly better performance of faculty versus fellows in each round (P-values of 0.04, <0.01, and <0.01 for rounds 1 to 3, respectively). Correct classification of NMs ranged from 31% to 92%, with statistically significantly better performance of faculty only in round 2 (P-values of 1.0, <0.01, and 0.61 for rounds 1 to 3, respectively). Correct classification of all cases combined ranged from 51% to 75% by morphology and 70% to 80% with p57, with statistically significantly better performance of faculty only in round 2 (P-values of 0.69, <0.01, and 0.15 for rounds 1 to 3, respectively). p57 immunostaining significantly improved recognition of CHMs (P<0.01) and had high reproducibility (κ=0.93 to 0.96) but had no impact on distinction of PHMs and NMs. Genotyping provides a definitive diagnosis for the ∼25% to 50% of cases that are misclassified by morphology, especially those that are also unresolved by p57 immunostaining.