In an effort to relate the protein profile to virulence, proteins from the cellular fractions and from culture supernatants of Streptococcus suis capsular type 2 strains from different geographical origins were compared by using Western blots (immunoblots). The protein profiles of the cellular fractions were similar for the majority of virulent and avirulent isolates studied, with the exception of three virulent Canadian strains for which a 135-kDa protein was not detected. Examination of the culture supernatants revealed the presence of a 135-kDa protein in all strains except the same three virulent Canadian isolates. In addition, a 110-kDa protein was present in 14 of 16 virulent strains and not in avirulent isolates. When injected into mice, the 110-kDa protein induced an immunoglobulin G response and protected against infection with homologous and heterologous virulent strains. Four strains (1330, 0891, TD10, and R75/S2) that were avirulent in the mouse model of infection and four other strains (1591, 999, JL590, and AAH4) that were virulent in the mouse model were injected into pigs. All virulent strains reproduced the disease, and all avirulent strains failed to reproduce the disease (with the exception of transient lameness in one case and fever in another case). The 110-kDa protein therefore appears to be a reliable virulence marker and a good candidate for a subunit vaccine.