Antibiotic exposure exerts strong selective pressure and is an important modifiable risk factor for antibiotic resistance. We aimed to identify the role of various antibiotics as risk factors for the isolation of extended-spectrum-beta-lactamase (ESBL)-producing Klebsiella spp. in hospitalized patients at a tertiary-care hospital. A parallel multivariable model was created to compare two groups of cases with either nosocomially acquired ESBL- or non-ESBL-producing Klebsiella spp. to a common control group of hospitalized patients (a case-case-control design). Seventy-eight ESBL cases, 358 non-ESBL cases, and 444 controls were analyzed. Significant factors associated with the isolation of Klebsiella spp. were an age of >65 years, transfer from a health care facility, an intensive care unit (ICU) stay, and the presence of a comorbid malignancy or lung, hepatic, or renal disease. A propensity score was generated from the above, and our ability to discriminate between Klebsiella cases and controls (area under the receiver-operating-characteristic [ROC] curve, 0.78) was good. The ESBL phenotype was tightly linked with fluoroquinolone resistance (95% versus 18%, P < 0.001). Factors associated with isolation of ESBL Klebsiella spp. in a multivariable analysis, adjusting for the propensity score, included exposure to beta-lactam-beta-lactamase inhibitor combinations (odds ratio [OR], 10.17; 95% confidence interval [CI], 1.19 to 86.92) and to fluoroquinolones (OR, 2.86; 95% CI, 1.37 to 5.97). Exposure to broad-spectrum cephalosporins was statistically associated with ESBL Klebsiella spp. only among the subgroup of patients not treated with fluoroquinolones. In our institution, where the ESBL-producing-Klebsiella phenotype is coselected with fluoroquinolone resistance, fluoroquinolone and beta-lactam-beta-lactamase inhibitor combinations, rather than cephalosporins, are the main risk factors for ESBL isolates. Formulary interventions to limit the spread of ESBL-producing isolates should be tailored to each setting.