Gestational diabetes mellitus (GDM) is still a clinical challenge around world. Inflammation contributes to the pathogenesis of GDM, the precise underlying mechanism remains to be explored. IL-37 and 38 play important role in autoimmunity, but their role in the development of GDM is unclear. Using histopathology and immunohistochemistry, the thickness of the umbilical artery, the area of capillaries within the placental chorionic villi, and the production of IL-37/38 were determined. Placental mRNA of IL-37/IL-38 from GDM and Non-GMD was measured using qRT-PCR. serum IL-37/IL38 levels were evaluated, using ELISA. IL-37 was reduced 49%, 48% or 57% in chorionic villi of placentas (P<0.05), umbilical artery (P<0.05), or umbilical vein (P<0.05) from GDM women, respectively, compared to that from non-GDM women. In contrast, IL-38 was increased 3.3, 2.6, or 2.6 fold in chorionic villi (P<0.01), umbilical artery (P<0.05), umbilical vein (P<0.05) from GDM women, respectively, compared to that from non-GDM women. IL-37 in GDM placentas or serum was reduced ∼52% or 33%, compared to that from Non-GDM subjects, respectively; whereas IL-38 in the GDM placentas or serum was increased by 1.6 fold or 1.3 fold, compare to that from Non-GDM, respectively. Our data suggest that IL-37 protect pregnant women from the development of GDM. IL-38 produced in the chorionic villi and umbilical cords may be a response to local inflammation during the development of GDM. Such a dysregulated micro-environment may contribute to the development of GDM via an immune-mediated mechanism. These data may provide useful information for the intervention for GDM.