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Extra-intestinal pathogenic E. coli cause urinary tract infections (UTIs), newborn meningitis, abdominal sepsis and septicemia. UTIs affect millions of women annually, and result in significant health care costs and morbidity worldwide. Uropathogenic E. coli (UPEC) is the predominant urinary tract pathogen, causing up to 85% of UTIs. Despite appropriate therapy, recurrent episode of UTI are common and bacterial strains are increasingly more resistant to many currently used antimicrobial agents. The pstSCAB-phoU operon encodes the phosphate specific transport system (Pst) and belongs to the Pho regulon, which is regulated by the two-component regulatory system (TCRS) PhoBR. Inactivation of the Pst system in E. coli and other bacteria leads to constitutive activation of the Pho regulon, perturbations in cellular adaptation, and decreased virulence. The role of the Pst system in uropathogenic E. coli (UPEC) was assessed by deleting the pstSCA genes in UPEC strain CFT073. In competitive (co-challenge) and single-strain infections, the pst mutant was attenuated for colonization of both the bladder and kidneys of CBA/J mice and was impaired for production of Type 1 fimbriae. Type 1 fimbriae are essential for UPEC virulence and their phase-variable expression is positively and negatively regulated by FimB and FimE, respectively. In vitro, in LB broth and human urine, repression of the fim structural gene fimA in the pst mutant correlated with increased orientation of the fim promoter in the OFF-position. In vivo, down-regulation of fimA in CFT073 Δpst correlated with the up-regulation of fimE. To confirm the specific role of repression of fim expression by the pst mutant during UTI, fim phase locked-ON pst derivatives of the pst mutant and WT CFT073 strains were constructed. Compared to the pst mutant, the fim phase locked-ON pst derivative demonstrated a significant gain in colonization of the bladder, that was similar to that of CFT073 WT and CFT073 fim locked-ON strains. As Type 1 fimbriae are important for UPEC virulence, by promoting adhesion, our results suggest that the reduced bladder colonization by the pst mutant during UTI is predominantly attributed to down-regulation of these fimbriae. Since the Pho regulon is controlled by the TCRS PhoBR, molecules inducing the expression of the Pho regulon through inactivation of Pst or activation of PhoBR could potentially impair UPEC virulence by inhibiting colonization and the infection cycle, which is dependent on expression of type 1 fimbrial adhesins.