To clarify the usefulness of histopathology in evaluating invasiveness during acute cystitis and pyelonephritis in a mouse model of urinary tract infection, findings from bladder and kidney sections of mice inoculated transurethrally with Escherichia coli were compared with results of bladder, kidney, spleen, and blood cultures and with changes in peripheral blood leukocyte counts. All of the 14 bladder histopathologic abnormalities evaluated were significantly associated with a positive bladder culture, and 7 were associated with splenic infection. Histopathologic features of cystitis were present in some culture-negative bladders. Eleven of 12 renal histopathologic abnormalities evaluated were significantly associated both with a positive kidney culture and with splenic infection, and two correlated with the development of peripheral leukocytosis. Histopathologic features of pyelitis and nephritis permitted culture-positive kidneys to be categorized as exhibiting colonization only, pyelitis only, or pyelitis plus frank nephritis and demonstrated that some culture-negative kidneys exhibit signs of pyelitis and nephritis. These findings suggest that detailed, semiquantitative histopathologic evaluation can add to quantitative cultures in the assessment of bacterial urovirulence in the mouse model of ascending urinary tract infection.