Previously, the PhoP-repressed locus prgH was identified as important for signalling epithelial cells to endocytose Salmonella typhimurium. Characterization of prgH revealed that it is an operon of four genes encoding polypeptides of 392 (prgH), 80 (prgl), 101 (prgJ) and 252 amino acid residues (prgK). Synthesis of the 2.6 kb prgHIJK transcript was repressed in bacteria that activate PhoP/PhoQ, indicating that PhoP/PhoQ regulates prgHIJK by transcriptional repression. The prgl, prgJ and prgK predicted gene products were similar to Shigella flexneri and Yersinia enterocolitica proteins required for secretion of lpa and Yop virulence factors. Analysis of the culture supernatants from wild-type S. typhimurium demonstrated that at least 25 polypeptides larger than 14 kDa could be detected. In contrast, prgH1::TnphoA, phoP-constitutive and hil-deletion mutants had significant defects in their supernatant protein profiles. The invasion and supernatant protein profile defects of the prgH1::TnphoA mutant were both complemented by a 5.1 kb plasmid that included prgHIJK. These results suggest that PhoP/PhoQ regulates extracellular transport of proteins by transcriptional repression of secretion determinants and that secreted proteins may be involved in signalling epithelial cells to endocytose bacteria.