This study investigated the proteomes of macro-, micro- and nanovesicles derived from the same first trimester human placenta to better understand the role that these extracellular vesicles (EVs) play in maternal adaptation during healthy pregnancy. During human pregnancy, the mother undergoes major physiological and immunological adaptations to accommodate the fetus. There is growing evidence that EVs extruded from the placental syncytiotrophoblast into the maternal blood may regulate these maternal adaptations. Placental EVs can be divided into macro-, micro- and nanovesicles based on their size. To date, it is unclear whether these differently sized EVs carry different protein cargos and have different effects on maternal responses.