A Japanese randomized controlled study showed that Interferon (a) over cap (IFN-(a) over cap 1b) therapy is clinically effective in decreasing the frequency of attacks in multiple sclerosis (MS), even in optico-spinal MS (OSMS). However, recent studies have shown that IFN-(a) over cap (IFN-(a) over cap 1a/IFN-(a) over cap 1b) treatment was not effective in neuromyelitis optica (NMO) patients and that the diminished benefit of IFN-(a) over cap. treatment in NMO may be due to different immune responses to IFN-(a) over cap. We determined longitudinally the expression of CCR5, CXCR3 and CCR4 on CD4+ T and CD8+ T cells in the blood from patients with NMO and MS treated with IFN-(a) over cap 1b. During a 12-month period of IFN-(a) over cap 1b therapy, the annualized relapse rate decreased in MS patients but not in NMO patients. There was no significant difference in the expression of the chemokine receptors between NMO and MS at baseline. The percentages of CD4+CCR5+ and CD4+CXCR3+ T cells, representative of the Th1 response, were decreased in both NMO and MS after treatment. The percentage of CD4+CCR4+ T cells, representative of the Th2 response, was decreased in MS, but those for NMO was significantly increased compared with the pretreatment levels. Our results indicate that IFN-(a) over cap 1b-induced up-modulation of the Th2 response in NMO patients may be the source of differences in the therapeutic response to IFN-(a) over cap 1b therapy. In the present study, Th2 predominance is involved in the pathogenesis of NMO.