Guillain-Barre Syndrome (GBS) is an inflammatory disease of the peripheral nervous system. Given that plasma metabolic profiles in GBS patients have never been explored, plasma samples of 38 GBS patients, 22 multiple sclerosis (MS) patients, and 40 healthy controls were analyzed by using untargeted and targeted metabolomics analysis. The untargeted analysis showed that levels of a set of plasma lipid metabolites were significantly decreased in GBS patients compared to the controls. Furthermore, the targeted analysis demonstrated that levels of 41 metabolites in GBS patients were significantly changed compared to either the controls or MS patients. A further metabolic analysis showed that 12 of 41 metabolites were significantly lower in classical GBS patients compared to Miller-Fisher syndrome. Among them, each of PCae C34:0, PCae C42:2, PCae C42:3, and SM C24:0 was inversely correlated with Hughes functional grading scale of GBS patients at both nadir and discharge. Receiver operating characteristic curve analysis of combination of three metabolites (PCaa C42:2, PCae C36:0 and SM C24:0) showed a good discrimination between the GBS and the controls (area under curve = 0.86). This study has demonstrated disruption of lipid metabolites in GBS may be potential biomarkers to indicate disease severity and prognosis of GBS.