Salmonella enterica serovar Typhi (S. Typhi) is the causative agent of human typhoid fever. S. Typhi expresses a major virulence determinant called Vi polysaccharide capsular antigen, which is encoded by the viaB locus containing 10 consecutive genes including tviA and tviB. Expression of Vi antigen is regulated by the two-component regulatory system EnvZ/OmpR and the global RNA-binding factor Hfq. In this study, we show that OmpR coordinates with Hfq to regulate the transcription of Vi antigen genes under osmotic stress conditions. OmpR binds to the promoters of tviA and its own genes to activate their transcription; however, it positively regulates tviB and negatively regulates hfq in an indirect manner. Moreover, Hfq reversely inhibits ompR, tviA and tviB, and positively regulates its own gene expression. Thus, we report of a complex gene regulatory network involving the reciprocal regulation and autoregulation of OmpR and Hfq, and their regulatory actions on Vi polysaccharide capsular antigen genes in S. Typhi.