Plasma exchange is used increasingly as an individual therapeutic decision for treating of severe, steroid-resistant relapses of multiple sclerosis (MS). However, given that its mechanism of action in this CD4+ T cell-mediated autoimmune disease remains unknown, it is not yet considered as a routine therapy for this prevalent neuroimmune disorder. In this regard, we hypothesized that plasma exchange, by depleting the body of inflammatory mediators that acts as providers of co-stimulatory signals for the adaptive immune system, provides the immune system with an exceptional break for de-novo recognition of autoantigens in a tolerogenic manner. This may lead to an increase in the frequency and function of myelin-specific regulatory T cells. For evaluating this we suggest some in vitro and in vivo studies to analyse the effects of varied dilutions of normal and MS plasmas on the induction of regulatory T cells or on the function of isolated and purified regulatory T cells. Clarifying the effects of therapeutic plasma exchange on regulatory T cells as the major controllers of autoimmune responses may provide us with strong evidence to use this procedure as a disease-modifying treatment in remission phase for reducing the rate and severity of future attacks, in addition to more trustworthy therapy in severe relapses of MS.