OBJECTIVE To determine the prevalence and clinical correlation of anti-calpastatin antibodies in patients with systemic sclerosis (SSc). METHODS Serum samples from patients with limited cutaneous SSc (lSSc; n=36), diffuse cutaneous SSc (dSSc; n=27), and healthy control subjects (n=29) were examined by an ELISA using human recombinant calpastatin as antigens. RESULTS IgG anti-calpastatin antibodies were positive in 15 (24%) of 63 patients with SSc, which was similar to the frequency of IgM anti-calpastatin antibody positivity (14/63, 22%). The presence of anticentromere antibodies was associated with the presence of IgG and/or IgM anti-calpastatin antibodies. The patients with SSc positive for IgG anti-calpastatin antibodies had significantly higher erythrocyte sedimentation rates (ESR) compared with those negative for IgG anti-calpastatin antibodies. Furthermore, the levels of IgG anti-calpastatin antibodies correlated positively with the levels of ESR. The patients with dSSc positive for IgM anti-calpastatin antibodies had significantly higher frequency of inflammatory joint and muscle involvement compared with those negative for IgM anti-calpastatin antibodies. Four (80%) of 5 patients with dSSc with both joint and muscle involvement produced IgM anti-calpastatin antibodies. CONCLUSIONS The presence of anti-calpastatin antibodies may be a clue to mechanisms of the inflammatory change occurring in SSc. Furthermore, the presence of anti-calpastatin antibodies could be a novel and useful serologic tool for recognizing patients with dSSc with inflammatory joint and muscle involvement.