With an intact normal bladder bacterial colonization is uncommon unless intermittent catheterization is instituted. Because intestine, which is normally colonized with bacteria, is used to form an orthotopic neobladder, we determined whether patients with orthotopic urinary diversion are at increased risk for urinary tract infection and urosepsis. A total of 66 patients who received an orthotopic neobladder after radical cystectomy were prospectively evaluated with urinalysis and culture 2 months to 4 years postoperatively. No patient was on suppressive antibiotics unless they had recurrent urinary tract infections. A total of 55 voided normally and 11 performed intermittent catheterization at least once daily due to high post-void residual urine. Of the patients who voided normally 78% had at least 1 positive urinalysis. If a patient had a positive urinalysis, bacteria was identified on culture in 50%. Overall 26 (39%) and 8 (12%) patients had a urinary tract infection and urosepsis, respectively. The estimated 5-year probability of urinary tract infection and urosepsis for patients who voided independently were 58% and 18%, respectively. Urine culture with greater than 100,000 cfu bacteria and female gender were the only factors predictive of urinary tract infection on multivariate analysis. Recurrent urinary tract infection was the only predictor for urosepsis. Intermittent catheterization or hydronephrosis was not related to urinary tract infection or urosepsis. The presence of small bowel intestine appears to promote asymptomatic bacterial colonization but urosepsis rarely occurs unless the patient has recurrent urinary tract infections. Prophylactic antibiotics are recommended only for patients with recurring urinary tract infections but treating a positive urinary culture in the absence of specific voiding symptoms is not advocated in this patient population.