Background: The hydatidiform moles remain prevalent in spectrum of gesta-tional trophoblastic diseases (GTDs). In resource-limited settings like Rwanda, the definitive diagnosis relies upon single of histomophological diagnosis. The histomorphology alone suffers from high interobserver and intra-observer vari-ability with poor diagnostic reproducibility. The present study aimed at deter-mining the role of p57 immunophenotyping in the validation of histomorpholog-ical diagnosis of hydatidiform moles. Methods: A retrospective cross-sectional study embarked for histological cases collected between January 2017 and June 2020. A review of Hematoxylin &Eosin(H&E) stained slides was performed with subsequent p57 immunohisto-chemical staining. Results: Recorded were 211 retrospective cases of hydatidiform moles and 96 (45.9%) cases were all subjected to p57 immunohistochemical staining consid-ered as gold standard diagnostic modality in the present study. As result, the sensitivity and specificity of the histomophological diagnosis of complete hyda-tidiform mole were estimated at 62.5% and 57.1% respectively with positive and negative likelihood ratio of 0.145 and of 0.54 respectively. PPV and NPV were 81.8% and 29.3%, respectively. Whereas of 57.1% and 79.2% with PPV and NPV of 42.9% and 83.8% respectively for partial hydatidiform moles. Per the Youden J statistics method, the accuracy estimation of histomophological diagnosis of hydatidiform mole (HM) was 0.196 (CHM) and 0.336(PHM). Conclusions: This study highlighted a need to integrate p57 immunostaining in routine histopathological diagnosis of hydatidiform moles refining the defini-tive diagnosis.