Antibodies directed against the streptococcal 42 kDa hyaluronate synthase and a 56 kDa auxiliary protein bound to the surface of intact human fibroblasts in vitro. Staining was most prominent during the detachment phase of mitosis. In eukaryotic plasma membranes a 52 kDa protein was recognized by the antiserum against the 56 kDa streptococcal protein. Since the cross-reacting proteins could be involved in immunological mimicry between streptococcal and human antigens leading to heart cell necrosis, the reactivity of sera from patients with rheumatic fever was compared with that of sera from healthy or streptococcal infected persons. The sera from patients with rheumatic fever showed a higher reactivity against the 56 kDa protein than those from healthy persons or from patients with an antibiotic treated streptococcal infection. This difference was not observed for the 42 kDa protein. These sera were able to lead to cell lysis in the presence of complement.