The aim of this work was to investigate the longitudinal evolution of plasmatic soluble HLA-G (sHLA-G: shed HLA-G1 plus HLA-G5) during pregnancy, and if peripheral maternal antigen presenting cells (APC) can be a source of sHLA-G. Blood samples were obtained from 45 volunteers during normal pregnancy, 8 of them monthly; from 8 pregnant volunteers in the first weeks of pregnancy who had later a miscarriage, and from 14 healthy nonpregnant control women. Monocytes obtained during pregnancy showed a moderately HLA-G cell surface expression and stimulation with interferon (IFN)-gamma increased this expression. Monocytes-derived dendritic cells obtained from pregnant women during the first and third trimester of pregnancy secreted more sHLA-G than those obtained from nonpregnant women. Plasmatic sHLA-G concentration in pregnant women was significatively higher than in nonpregnant women, with a peak in the third month. We can conclude that maternal APC are a source of sHLA-G. Women who experienced miscarriage had previously very low or undetectable plasmatic sHLA-G levels in the second month of pregnancy. Data suggest that undetectable sHLA-G could be a risk of complications.