Streptomycin, gentamicin, and tetracycline are currently considered the antimicrobials of choice for the treatment of tularemia. Preliminary data suggest that quinolones may be effective alternative agents; however, clinical experience is limited, and their role in treating severe disease is uncertain. We recently treated two acutely ill immunocompromised patients who had presumed "atypical" pneumonia with levofloxacin. Both patients had an excellent clinical response and were diagnosed with tularemia only when blood cultures subsequently yielded Francisella tularensis. Neither patient relapsed during 12 months of follow-up. Including our two cases, a total of 10 cases of tularemia treated with quinolones have been reported. In all 10 cases, a favorable clinical response was documented, and no relapses occurred. We conclude that the quinolones appear promising for the treatment of even severe tularemia, and they should be considered efficacious alternative agents for patients who do not require parenteral therapy or are intolerant of more standard treatment regimens.