Alpha-2-macroglobulin (A2M) is a proteinase inhibitor involved in deactivation of cytokines and modulation of antigen-mediated immune responses. Based on its role in inflammatory and neurodegenerative disorders, we investigated the role of A2M and its receptor low-density lipoprotein receptor-related protein (LRP) for the development of multiple sclerosis (MS). We analyzed the frequency of two polymorphisms in the A2M (Val 1000 Ile, Exon 18 del), and one polymorphism in the LRP (A216V) gene in a case control study involving 326 MS patients, and 290 controls, all defined for the expression of HLA-DR15. No association was found for any of the three polymorphism with MS. Furthermore, no differences in serum A2M levels were detected between MS patients and controls. The results do not suggest a contribution of A2M and LRP to the development of MS.