Fluoroquinolone resistance in Moraxella catarrhalis isolates has been quite rare. This report presents a case history of a 22-year-old man with compromised immune status and severe pneumonia caused by M. catarrhalis. The organism was markedly resistant (MICs, 1.5- > 32 micrograms/mL) to several marketed fluoroquinolones including the agent (levofloxacin) used for concurrent and prior therapy. The emergence of this problematic strain seems related to chronic exposure of the patient to compounds in the class and poor patient compliance to prescribed medications. The strain was not clonally related to other M. catarrhalis strains isolated in the same hospital during early 1998. This second documented case of a fluoroquinolone-resistant M. catarrhalis clinical isolate presents a warning that resistances can emerge in at-risk patients, and that surveillance systems (SENTRY) will be necessary to monitor for unusual organisms and spread of resistance phenotypes among commonly isolated respiratory tract pathogens.