Streptococcus suis serotype 2 (SS2) is a zoonotic pathogen responsible for a spectrum of disease in pigs and that can be transmitted to humans with fatal consequences. Despite the socioeconomic importance of this infection, the pathogenesis of SS2 is poorly understood. The protein SsPep (05SSU0153) has been characterized as an extracellular protein. A deletion mutant of the gene encoding SsPep showed significantly decreased virulence in the pig infection model. Three groups challenged with different doses 5 × 10(5) CFU, 1 × 10(6) CFU, and 5 × 10(6) CFU of the wild type strain, as the results all the pigs died, while those given the SsPep deletion mutant all survived challenge with 5 × 10(5) CFU and 1 × 10(6) CFU doses; four pig in the high dose group challenged with 5 × 10(6) CFU and two pigs died at last. These findings suggest that SsPep plays a critical role in the pathogenesis of SS2.