Background: Lack of resolution of inflammation may be considered a critical player for the onset and progression of multiple sclerosis. To demonstrate this we extracted lipids from plasma samples of healthy donors and MS patients and we quantified over 65 lipid mediators (LMs) through LC-MS-MS using signature diagnostic ions via multiple reaction monitoring. Results: Out of the 65 lipid mediators analyzed, only 42 were detected and out of those only 27 were finally revealed to show differences between healthy subjects and MS patients. These 27 LMs belonged to the arachidonic (AA), docosahexaenoic (DHA) or eicosapentaenoic (EPA) acid metabolomes and we could clusterize each form of MS into a specific profile by means of principal component analysis. Altogether, compared to healthy subjects, MS patients showed a strong production of several AA-derived eicosanoids (i.e. PGE2, PGD2 and PGF2a) (Fig.1D) and a little production of two DHA-derived pro-resolving mediators (SPMs), i.e. Protectin D1 (D1) and protectin DX (PDX) (Fig.1A). However, no production of DHA-derived resolvins and maresins (Fig. 1B) as well as EPA-derived resolvins (Fig.1 C) was observed. When stratifying MS patients according to disease form, both relapsing MS patients showed production of only two pro-resolving mediators (SPMs), i.e. Resolvin D1 (RvD1) and Protectin D1 (D1) compared to healthy subjects, whereas remitting MS patients showed a production of only few AA- and DHA-derived metabolic pathway markers and progressive MS patients a strong production of several eicosanoids as well as other metabolic pathway markers. Conclusions: These data suggest that along disease progression, there is a lack of production of anti-inflammatory and pro-resolving lipid mediators associated to a higher production of pro-inflammatory ones.