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Introduction The low-density lipoprotein receptor-related protein 5 (LRP5) and its inhibitor sclerostin, are key components of bone metabolism and potential contributors to type 2 diabetes mellitus susceptibility. This study aims at evaluating the expression of placental LRP5 and sclerostin in pregnancies with gestational diabetes mellitus (GDM) and investigate possible associations with umbilical sclerostin concentrations and clinical outcomes in mothers and their neonates. Methods Twenty-six GDM-mothers and 34 non-GDM mothers of Caucasian origin and their neonates admitted in a Gynecology and Obstetrics Department of a university hospital were included in this study. Demographic data and maternal fasting glucose concentrations (24-28 weeks of gestation) were retrieved from the patients’ medical records. Placental LRP5 was determined by immunohistochemistry (IHC) and Western blotting (WB) analysis, while placental sclerostin by IHC. Umbilical serum sclerostin concentrations were measured by ELISA. Results Placental sclerostin IHC intensity values were positively correlated with LRP5 values as detected either by IHC (r=0.529; p<0.001) or WB (r=0.398; p=0.008), with pregestational maternal BMI values (r=0.299; p=0.043) and with maternal fasting glucose concentrations (r=0.475; p=0.009). Placental sclerostin and LRP5 were significantly greater in GDM compared to non-GDM placentas (h-score: 65.08±17.09 vs. 11.45±2.33, p<0.001; 145.53±43.74 vs. 202.88±58.65, p<0.001; respectively). Discussion Sclerostin and LRP5 were detected in human placentas. The overexpression of placental sclerostin and LRP5 values in GDM compared to non-GDM pregnancies, as well as the positive association of placental sclerostin values with pregestational maternal BMI and maternal fasting glucose concentrations may indicate the development of an adaptive mechanism in face of maternal hyperglycemia.