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We describe a clonal outbreak of quinolone-resistant Haemophilus influenzae (QRHI) from an affiliated long-term care facility (LTCF-A); the outbreak was associated with the clinical use of levofloxacin, which was determined to be a risk factor for acquisition of QRHI. The minimum inhibitory concentration to which 90% of isolates were susceptible (MIC90), as determined by broth microdilution, was >4 μg/mL for levofloxacin, >2 μg/mL for moxifloxacin, >2 μg/mL for gatifloxacin, and 8 μg/mL for gemifloxacin. The MIC90, as determined by Etest (AB Biodisk), was >32 μg/mL for levofloxacin, ciprofloxacin, moxifloxacin, and gatifloxacin. Having been a resident at LTCF-A and having chronic obstructive pulmonary disease were significant risk factors for acquisition of QRHI at our 500-bed hospital (New York Hospital Queens). All QRHI isolates were found to be genetically related by pulsed-field gel electrophoresis, were nontypeable, were susceptible to ceftriaxone and azithromycin, and were negative for β-lactamase production. Emphasis on patient contact and respiratory isolation and placing colonized or infected patients in cohorts yielded a marked reduction in the prevalence of QRHI at LTCF-A.