Streptococcal histidine triad protein was identified recently as a cell surface-associated protein family. Five members of this family (PhtA, PhtB, PhtD, PhtE and HtpA), derived from Streptococcus pneumoniae and Streptococcus pyogenes, have been shown as antigens that confer protection to the host on infection. In this report, a gene sequence highly homologous to htpA and phtD (designated htpS, the histidine triad protein of Streptococcus suis) was identified from S. suis 2 Chinese strain 05ZYH33. Our data revealed that htpS is extremely conserved in S. suis 2 and widely distributed in 83% (29/35) of 35 S. suis serotypes. It was also demonstrated by Western blot and flow cytometry that HtpS is a cell surface-associated protein that was expressed during S. suis 2 infection. An antibody against HtpS could increase the deposition of human complement 3 on S. suis 2 and also enhance the clearance of S. suis 2 in whole blood. In addition, mice could be immunized against S. suis 2 infection and were well protected after immunization with recombinant HtpS.