Salmonella typhi is the causative agent of typhoid fever in humans. A cellculture based assay involving the human monocyte macrophage cell line U937 has been developed to examine S. typhi invasion and survival. An 5. typhi PhoP' (null) mutant was shown to be restricted in net growth in phorbol myristate acetate (PMA) differentiated U937 (PMA4937) cells, and an 5. typhi PhoPC (constitutive) mutant showed a defect in invasion. Neither of the phoPIQ mutants were growth impaired in HeLa cells, however the PhoPc mutant was impaired in invasion. As opposed to what was found for S. typhi, Salmonella typhimurium wild-type, PhoP' and PhoPc mutants grew equally well in PMA4937 cells, indicating that the PhoP--mediated net growth restriction in the PMA4937 cells was S. typhi specific. An S. typhi mutation, pqaB::MudJ, recently shown t o be a PhoP-activated locus, was shown to have a net growth defect in PMA4937 cells. Sequencing of the S. typhipqaB gene revealed it had 98% identity to the fifth gene in a S. typhimurium PmrA/B regulated operon necessary for 4-aminoarabinose lipid A modification and polymyxin B resistance. The pqaB locus was regulated by PmrA/B (whose activity is modulated by PhoP-PhoQ) and the pqaB transposon mutant was sensitive to polymyxin B. The lipopolysaccharides (LPS) of 5. @phi and S. typhimurium wildtype, PhoP' and PhoPc mutants, were compared by SDS-PAGE and silver staining. Differences in the LPS profile between the two Salmonella species were observed, and shown to be affected differently by the PhoPc mutation. Additionally, the pqaB:: MudJ mutation affected S. typhi LPS. The effects on LPS may have ramifications for the difference between S. typhi and S. typhimurium infection of hosts.