A case-control study was conducted to identify the risk factors associated with levofloxacin-resistant Streptococcus pneumoniae (LRSP) colonization or infection. Twenty-seven case patients (patients with LRSP) were compared with 54 controls (patients with levofloxacin-susceptible S. pneumoniae). Risk factors that were significantly associated with LRSP colonization or infection, according to univariate analysis, included an older age (median age, 75 years for case patients versus 72.5 years for controls), residence in a nursing home (odds ratio [OR], 7.2), history of recent (OR, 4.6) and multiple (OR, 4.4) hospitalizations, prior exposure to fluoroquinolones (OR, 10.6) and beta-lactams (OR, 8.6), presence of chronic obstructive pulmonary disease (COPD; OR, 5.9), and nosocomial origin of the bacteria (OR, 5.7). Multivariate analysis showed that presence of COPD (OR, 10.3), nosocomial origin of the bacteria (OR, 16.2), residence in a nursing home (OR, 7.4), and exposure to fluoroquinolones (OR, 10.7) were independently associated with LRSP colonization or infection. Thus, a distinct group of patients with COPD is the reservoir of LRSP.