Maternal hyperglycemia during pregnancy is associated with excess fetal growth and adverse perinatal and developmental outcomes. Placental epigenetic maladaptation may underlie these associations. We performed an epigenome-wide association study (>850,000 CpG sites) of term placentas and prenatal maternal glycemic response 2-hour post oral glucose challenge at 24-30 weeks of gestation among 448 mother-infant pairs. Maternal 2-hour glycemia post-load was strongly associated with lower DNA methylation of 4 CpGs (FDR q<0.05) within the Phosphodiesterase 4B gene (PDE4B). Additionally, three other individual CpG sites were differentially methylated relative to maternal glucose response within the TNFRSF1B; LDLR; and BLM genes (FDR q<0.05). DNA methylation correlated with expression of its respective genes in placental tissue at 3 out of 4 independent identified loci: PDE4B (r: 0.31, P<0.01), TNFRSF1B (r: -0.24, P=0.013) and LDLR (r: 0.32, P<0.001). In an independent replication cohort (N= 65 to 108 samples), results were consistent in direction but not significantly replicated among tested CpGs in PDE4B and TNFRSF1B Our study provides evidence that maternal glycemic response during pregnancy is associated with placental DNA methylation of key inflammatory genes whose expression levels are partially under epigenetic control.