Streptococcus suis serotype 2 (S. suis 2) has evolved into a highly invasive pathogen that was found to be the cause of 2 large-scale outbreaks of streptococcus toxic shock syndrome (STSS) in China. However, the mechanism of action of this non-group A streptococcal (GAS) S. suis-caused STSS is still unknown. Previously, we identified a unique pathogenicity island (PAI) designated 89K that is specific to the STSS-causing epidemic strains of S. suis 2. In this study, we further report a functional type IV-like secretion system (T4SS-like system) harbored in the 89K PAI that contributes to the development of STSS. Knockout of the 2 key components (VirD4-89K and VirB4-89K) of the T4SS-like system eliminated the lethality of the highly virulent strain and impaired its ability to trigger host immune response in experimental infection of mice. Our findings provide a new insight into the pathogenesis of STSS caused by the highly pathogenic S. suis 2 isolates.