Four Streptococcus pneumoniae genes, phtA, phtB, phtD, and phtE, as well as the slr gene of group A streptococci (GAS), encode proteins with a histidine triad motif (HxxHxH). Pht proteins function as protective antigens against S. pneumoniae infection. A search of the GAS genome database identified a novel protein, HtpA, possessing five histidine triad motifs. The htpA gene was shown to encode a 92.5-kDa protein located downstream of the fbaA and lbp genes, while Western blot analyses revealed that HtpA protein was expressed on the cell surfaces of all group A, B, C, and G streptococcal isolates tested. Immunization of mice with rHtpA induced antigen-specific antibody production and was effective after a single immunization, with antibody titers remaining constant for at least 84days. In addition, HtpA-immunized mice survived after challenge with GAS strains isolated from patients with streptococcal toxic shock syndrome for significantly longer periods than sham-immunized mice. In that experiment, the HtpA-specific antibody was effectively induced by a single immunization and the specific antibody titer remained constant for at least 84days. These results indicate that the novel histidine triad protein HtpA is a candidate vaccine for GAS infection.