To evaluate the invasiveness of ciprofloxacin-resistant Escherichia coli isolated from the urinary tract, the susceptibility to ciprofloxacin of Escherichia coli strains from patients with invasive urinary tract infection was compared with that of isolates from patients with noninvasive disease. In a 14-month period, 2054 different isolates of Escherichia coli were analyzed, of which 554 (27%) were resistant to ciprofloxacin. One hundred twelve (5.4%) strains were isolated from patients with invasive disease. Resistance was significantly less frequent in isolates from patients with invasive disease (4.5%) than in isolates from patients with noninvasive disease (28.3%) (OR, 0.12; CI 95%, 0.05-0.29; P<0.001). Most ciprofloxacin-resistant strains associated with invasive disease were isolated from bacteremic patients who had recently undergone an invasive procedure involving the urinary tract. Invasive disease is caused more frequently by ciprofloxacin-susceptible strains of Escherichia coli, suggesting that resistance to ciprofloxacin may decrease the invasiveness of uropathogenic Escherichia coli.