Streptococcus suis serotype 2 is an important porcine bacterial pathogen and zoonotic agent mainly responsible for sudden death, septic shock, and meningitis, with exacerbated inflammation being a hallmark of the infection. However, serotype 2 strains are genotypically and phenotypically heterogeneous with varying virulence levels. Though type I interferons (IFNs) are traditionally associated with important anti-viral functions, recent studies have demonstrated that they may also play an important role during infections with extracellular bacteria. Herein, the implication of IFN-beta in the S. suis serotype 2 pathogenesis, which has always been considered a strict extracellular bacterium, was evaluated using strains of varying virulence. This study demonstrates that intermediate virulence strains are significantly more susceptible to phagocytosis than virulent strains. Hence, subsequent localization of these strains within the phagosome results in recognition of bacterial nucleic acids by Toll-like receptors 7 and 9, leading to activation of the interferon regulatory factors 1, 3, and 7 and production of IFN‑beta. Type I IFN, whose implication depends on the virulence level of the S. suis strain, is involved in host defense by participating in the modulation of systemic inflammation, which is responsible for clearance of blood bacterial burden. As such, when induced by intermediate, and to a lesser extent, virulent S. suis strains, type I IFN plays a beneficial role in host survival. Meanwhile, the highly virulent strain responsible for the 2005 human outbreak hastily induces a septic shock that cannot be controlled by type I IFN, leading to rapid death of the host