Recent studies demonstrated that dysregulation of NKG2D and its ligands, leading to activation of autoreactive effector cells, can trigger autoimmune diseases, but soluble forms of these ligands can downmodulate NKG2D expression in T effector cells. We investigated the presence of soluble major histocompatibility complex class I chain-related A or B (MICA or MICB) molecules in sera of multiple sclerosis (MS) patients and whether they play a role in the progression of the disease. Although soluble MICA serum levels did not differ, soluble MICB serum levels were higher in MS patients compared with controls. Moreover, the highest MICB levels were in MS patients during relapses. Using immunohistochemistry techniques, it was possible to locate MIC expression in neurons of MS demyelinating plaques that were intracellularly accumulated. Elevated soluble MICB levels exist in serum of multiple sclerosis patients related with disease activity. This may contribute to the modulation of immune response activity during relapses.