Tularemia, an infection caused by the coccobacillus Francisella tularensis, can be a difficult disease process to diagnose and treat. The difficulty in treating this disease is related to the pathophysiology of the infection and the toxicity of the antimicrobial agents presently recommended for treatment. Recent in vitro data have suggested that antimicrobial drugs other than standard agents (streptomycin, gentamicin, chloramphenicol, or tetracycline) may be effective. We present eight cases of documented failure of outpatient use of ceftriaxone in the treatment of tularemia. Our data suggest that while ceftriaxone may have excellent MICs in vitro, these MICs do not necessarily correlate with successful in vivo outcomes.