Description: Background: Metal ions are important micronutrients in cellular metabolism, but excess ions that cause toxic reactive oxygen species are harmful to cells. In bacteria, Fur family proteins such as Fur, Zur and PerR manage the iron and zinc uptake and oxidative stress responses,respectively. The single Fur-like protein (annotated as PerR) in Streptococcus suis has been demonstrated to be involved in zinc and iron uptake in previous studies, but the reports on oxidative stress response and gene regulation are limited. Results: In the present study, the perR gene deletion mutant [increment]perR was constructed in Streptococcus suis serotype 2 strain SC-19, and the mutant strain [increment]perR exhibited less sensitivity to H2O2 stress compared to the wild-type. The dpr and metQIN were found to be upregulated in the [increment]perR strain compared with SC-19. Electrophoretic mobility shift assays showed that the promoters of dpr and metQIN could be bound by the PerR protein. These results suggest that dpr and metQIN are members of the PerR regulon of S. suis. dpr encodes a Dps-like peroxide resistance protein, and the dpr knockout strains ([increment]dpr and [increment]dpr[increment]perR) were highly sensitive to H2O2. MetQIN is a methionine transporter, and the increased utilization of methionine in the [increment]perR strain indirectly affected the peroxide resistance. Using a promoter-EGFP genefusion reporting system, we found that the PerR regulon was induced by H2O2, and the induction was modulated by metal ions. Finally, we found that the pathogenicity of the perRmutant was attenuated and easily cleared by mice. Conclusions: These data strongly suggest that the Fur-like protein PerR directly regulates dpr and metQIN and plays a crucial role in oxidative stress response in S. suis.