© 2016 Royal College of Pathologists of AustralasiaThe distinction between partial hydatidiform mole (PHM) and trisomy gestation is not always straightforward histologically and it is unclear which morphological features, alone or in combination, provide the greatest diagnostic accuracy. We performed a comparative review of 89 products of conception (POC) specimens including 54 PHMs and 35 trisomy gestations, assessing the following in each case: trophoblastic atypia, cistern formation, multifocal trophoblast proliferation, lace-like trophoblast, villous enlargement, large trophoblast inclusions, scalloped villous shape, stromal apoptosis, small round villous inclusions, and fibrillary stromal collagen. There was a significant difference in the presence of trophoblast atypia, cistern formation, multifocal trophoblast proliferation, lace-like trophoblast, large trophoblastic inclusions, small round villous inclusions, fibrillary collagen (all p <0.01), and apoptosis (p = 0.028), between PHM and trisomy cases. Fibrillary collagen was more common in trisomy specimens whereas the other features were more common in PHMs. There was no significant difference in villous enlargement or scalloped villous shape between the two groups. The combination of cistern formation, multifocal trophoblast proliferation and large trophoblast inclusions correctly classified 83 (93.3%) of cases where the presence of at least two features was considered diagnostic of PHM. While cytogenetic analysis is arguably the gold standard for diagnosis, this study demonstrates that histological assessment permits accurate distinction of PHM and trisomic gestations in the great majority of cases.