We used microarray analysis to obtain insights into the immuno-regulatory mechanisms controlling pregnancy-associated MS disease activity. We studied expression levels of 5000 immune-related genes in peripheral blood mononuclear cells in patients with relapsing-remitting MS during pregnancy and postpartum and in comparison to controls. In the microarray analysis, HLA-G, a non-classical major histocompatibility molecule mainly attributed with immune-tolerogenic functions, was found differentially regulated between MS patients and controls. The finding was corroborated and extended by real-time PCR, flow-cytometry and ELISA in a larger patient sample. The results delineate an important role for the immune-tolerogenic molecule HLA-G in modulating disease activity and pregnancy-related changes in MS patients.