Protocadherins are transmembrane proteins exhibiting homophilic adhesive activities through their extracellular domain. Pcdh12 is expressed in angiogenic endothelial cells, mesangial cells of kidney glomeruli and glycogen cells of the mouse placenta. To get insights into the role of this protein in vivo, we analyzed PCDH12-deficient mice and investigated their placental phenotype. The mice were alive and fertile, however placental and embryonic sizes were reduced compared to wild types. We observed defects in placental layer segregation and a decreased vascularization of the labyrinth associated with a reduction in cell density in this layer. To understand the molecular events responsible for the phenotypic alterations observed in Pcdh12^-/- placentas, we analyzed the expression profile of E12.5 mutant placentas in comparison with wild types, using pangenomic chips. 2,289 genes exhibited statistically significant changes in expressed levels due to loss of PCDH12. Functional grouping of modified genes was obtained by GoMiner software. Gene clusters that contained most of the differentially expressed genes were those involved in tissue morphogenesis and development, angiogenesis, cell-matrix adhesion and migration, immune response and chromatin remodeling. Our data show that loss of PCDH12 leads to morphological alterations of the placenta and to notable changes in its gene expression profile. Specific genes emerging from the microarray screen support the biological modifications observed in PCDH12-deficient placentas.