Cytotoxic T lymphocyte associated antigen-4 (CTLA-4) is a costimulatory receptor transducing a potent inhibitory signal. Increasing evidence showed that CTLA-4 gene is an important susceptibility locus for autoimmune disorders. Alternatively spliced mRNA generates a soluble form, called sCTLA-4. Whereas low levels of sCTLA-4 are detected in normal human serum, increased/high serum levels are observed in several autoimmune diseases. The biological significance of increased sCTLA-4 serum level is not fully clarified yet. It can be envisaged that sCTLA-4 specifically inhibits the early T-cell activation by blocking the interaction of CD80/CD86 with the costimulatory receptor CD28. On the other hand, higher levels of sCTLA-4 could contend the binding of the membrane form of CTLA-4 with CD80/CD86, in later activation phase, causing a reduction of inhibitory signalling. We showed that sCTLA-4 from sera of patients with different autoimmune diseases is able to display functional activities on an in vitro system acting on the proliferation capability and modulating the secretion of cytokines. We observed a dual effect of sCTLA-4: inhibiting the secretion of IFN-γ , IL-2, IL-7, and IL-13 and activating the secretion of TGF-β and IL-10. This study underlines the role of sCTLA-4 in modulating the immune response and its relevance in autoimmune disease pathogenesis.