Recently we described an enzyme-linked immunoadsorbent spot (ELISPOT) assay allowing us to define an immunological response profile observed in multiple sclerosis patients treated with Copaxone (glatiramer acetate; GA) but not untreated subjects [4]. The profile encompasses three criteria, a) reduced proliferative response to GA (as observed with a standard primary proliferation assay); b) strong in vitro activation of interferon-γ-producing T cells at high concentrations of GA (as detected by interferon-γ ELISPOT); and c) activation of interleukin–4-producing T cells over a wider range of concentrations of GA (as detected by interleukin–4 ELISPOT). It is at present unknown whether the immunological response to GA correlates with the clinical response. To address this question we performed the pilot study reported here. We asked the major German multiple sclerosis centres to send us blood samples from all GA-treated patients who were going to discontinue treatment because of treatment failure. The clinical nonresponders either had an unchanged or increased exacerbation rate, or developed a secondary progressive course during GA treatment. Over more than one year, we prospectively collected 9 samples from clinical non-responders. We compared the immune response to GA of peripheral blood mononuclear cells from the 9 clinical nonresponders with 15 clinical responders, using a standard proliferation assay combined with ELISPOT assays for detection of interferon-γ and interleukin–4 secreting cells. Thirteen (86 %) of the 15 clinical responders met at least 2 of the immunological response criteria mentioned above. In contrast, only 2 (22 %) of the 9 clinical nonresponders met two of the immunological criteria (p = 0.0006). We conclude that the ELISPOT assay may provide a promising additional tool for monitoring the treatment response in multiple sclerosis patients treated with GA.