The effect of fluoroquinolone use on the susceptibility of Pseudomonas aeruginosa to fluoroquinolones in U.S. hospitals was studied. Benchmarking surveys were sent annually to pharmacists practicing in U.S. hospitals from 1993 to 1999. Data collected included hospital characteristics, antimicrobial expenditures and use, antimicrobial stewardship activities, and bacterial susceptibilities. Antimicrobial expenditures were normalized for the number of occupied beds (OBs) per year. General linear modeling and repeated-measures mixed-effects modeling were used to determine factors predictive of P. aeruginosa susceptibility to fluoroquinolones. A total of 174 hospitals provided data for fluoroquinolone expenditures and susceptibility of P. aeruginosa; the median number of years of data was 3 (range, 1-6), representing 416 hospital years. Community hospitals contributed a majority of the data. Median fluoroquinolone expenditures increased gradually from $230 per OB in 1993 to $400 per OB in 1998. A 55% increase to $620 per OB occurred in 1999, largely because of increased spending on levofloxacin. Susceptibility to ciprofloxacin was commonly used to assess fluoroquinolone susceptibility. The median susceptibility of P. aeruginosa to ciprofloxacin decreased from 84% to 71%. Increasing expenditures for ofloxacin and levofloxacin, but not ciprofloxacin, were associated with decreasing P. aeruginosa susceptibility to ciprofloxacin. In the final multivariable model, each study year after 1993 and every increase in ofloxacin expenditure of $100 per OB were associated with decreases in P. aeruginosa susceptibility. Data from a benchmarking survey of U.S. hospitals for 1993-1999 revealed increases in levofloxacin expenditures, total fluoroquinolone expenditures, expenditures for nonfluoroquinolone antipseudomonal antimicrobials, and total antimicrobial expenditures in 1999. Increases in expenditures for levofloxacin and ofloxacin were associated with a significant decrease in P. aeruginosa susceptibility to ciprofloxacin.