Antimicrobial resistance is an emerging problem with Pseudomonas aeruginosa. This study determined risk factors for the recovery of piperacillin-tazobactam-resistant P. aeruginosa from clinical cultures from hospitalized patients. A case-control study design was used to compare two groups of case patients with control patients. The first group of case patients was defined by nosocomial isolation of piperacillin-tazobactam-resistant P. aeruginosa, and the second group of cases yielded piperacillin-tazobactam-susceptible P. aeruginosa. Controls were selected in a 6:1 ratio from the same medical or surgical services among which piperacillin-tazobactam-resistant P. aeruginosa arose in patients. Risk factors analyzed included antimicrobial drug exposure, comorbid conditions, and demographics. Bivariate and multivariable analyses were performed. Piperacillin-tazobactam-resistant P. aeruginosa was isolated from 179 patients, and piperacillin-tazobactam-susceptible P. aeruginosa was isolated from 624 patients over a 2.5-year period. Piperacillin-tazobactam (odds ratio [OR] = 6.82; 95% confidence interval [CI], 4.56 to 10.21), imipenem (OR = 2.42; 95% CI, 1.19 to 4.94), aminoglycosides (OR = 2.18; 95% CI, 1.44 to 3.28), vancomycin (OR = 1.87; 95% CI, 1.21 to 2.89), and broad-spectrum cephalosporins (OR = 2.38; 95% CI, 1.45 to 3.88) were the antibiotics associated with the isolation of piperacillin-tazobactam-resistant P. aeruginosa. Exposure to vancomycin (OR = 1.53; 95% CI, 1.13 to 2.06) or ampicillin-sulbactam (OR = 2.28; 95% CI, 1.62 to 3.21) was associated with recovery of piperacillin-tazobactam-susceptible P. aeruginosa. In this study, antibiotics associated with piperacillin-tazobactam-susceptible P. aeruginosa were different from antibiotics associated with piperacillin-tazobactam-resistant P. aeruginosa. Piperacillin-tazobactam was a strong risk factor for piperacillin-tazobactam-resistant P. aeruginosa. Our results suggest that the nosocomial isolation of piperacillin-tazobactam-resistant P. aeruginosa may be affected by multiple antibiotics.