Multiple sclerosis (MS) is a complex autoimmune disease characterized by the destruction of the myelin sheath of neurons. Interferon beta (IFN-beta) is currently the major drug used to treat MS. Some patients fail to respond to this treatment, in some cases due to the development of neutralizing antibodies (NAb) to IFN-beta. We used microarray analysis and RT-PCR to measure gene expression in whole blood, 9-15 h postinjection, in patients with and without NAbs to IFN-beta. The canonical marker of biological response to IFN-beta, myxovirus resistance protein A, was upregulated in all NAb- patients while remaining unchanged in NAb+ patients. Genes functioning in immune response pathways were dominant in the set of differentially expressed genes: 73 immune response genes were identified as upregulated and 29 genes were identified as downregulated. B-cell activating factor (BAFF) is a strong candidate marker for biological and clinical response as well as for predisposition to NAb development. We demonstrate that it is responsive to IFN-beta in vitro and in vivo, and that its soluble form is elevated in serum from NAb- but not NAb+ patients. We conclude BAFF is a good biomarker for IFN-beta response, and requires further studies to determine its value as a marker for clinical response and NAb predisposition.