Interferon (IFN)-β treatment is effective in relapsing-remitting multiple sclerosis (RR-MS) via an as yet unidentified mechanism. In the present study, we investigated whether the expression of messenger RNA (mRNA) encoding the interleukin (IL)-12 subunits p40 and p35, IL-12 receptor chains, IL-18, tumor necrosis factor-α (TNFα), IFNγ, IL-10, IL-4, or transforming growth factor-β in unstimulated whole blood of 26 RR-MS patents changed during 6 months of IFNβ-1b treatment. In these patients, a significant change was found in TNFα mRNA, whereas changes in IL-12 receptor-β2 and IL-10 mRNA showed a trend. IFNβ-1b-related changes in cytokine mRNA expression were next evaluated in clinical subgroups of RR-MS patents classified as either clinical responders or nonresponders on the basis of Expanded Disability Status Scale progression and the number of relapses and steroid interventions needed in the 2 years before initiation of treatment compared with the 2 years after initiation of treatment. These subgroups showed different response patterns to IFNβ-1b treatment with respect to IL-10, TNFα, and IL-18 only. Surprisingly, clinical responders displayed no change in these cytokines, whereas nonresponders showed a decrease in TNFα and IL-18 mRNA as well as a transient increase in IL-10 mRNA. Baseline levels of IL-12p35 mRNA were lower in the responders compared with the nonresponders: this marker correctly predicted the clinical outcome in 81% of the 26 patents under investigation. Chemicals/CAS: interferon beta 1a, 145258-61-3; interferon beta-1b, 145155-23-3; Interferon-beta, 77238-31-4; Interleukin-12, 187348-17-0; RNA, Messenger