Group A streptococci (GAS) of serotypes most commonly associated with rheumatic fever (RF) outbreaks differ from many other serotypes by the presence of a unique, surface-exposed epitope on the M protein molecule. Based on the presence or absence of this epitope, GAS are categorized as class I or II, respectively. The objective of this study was to determine whether RF patients have an altered immune response to the class I-specific epitope. Immunoreactivity to class I- and class II-specific epitopes was determined for serum IgG derived from persons with a recent history of acute RF, uncomplicated GAS pharyngitis, and no known recent GAS infection. The results indicate that only RF patients display elevated levels of serum IgG directed towards the class I-specific epitope; they lack immunoreactivity to the class II epitope. The serologic findings strongly suggest that many of the RF patients were recently infected with a class I GAS isolate.