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Streptomycin, an antimicrobial with limited availability, is the treatment of choice for plague, a fulminating and potentially epidemic disease that poses a bioterrorism concern. We evaluated the efficacy of gentamicin and tetracyclines for treating human plague. A medical record review was conducted on all 75 patients with plague who were reported in New Mexico during 1985–1999. Fifty patients were included in an analysis that compared streptomycin-treated patients (n = 14) with those treated with gentamicin and/or a tetracycline (n = 36). The mean numbers of fever days, hospital days, and complications and the number of deaths did not differ between patients treated with streptomycin and those treated with gentamicin. One patient who received tetracycline alone experienced a serious complication. Gentamicin alone or in combination with a tetracycline was as efficacious as streptomycin for treating human plague. The efficacy of a tetracycline alone could not be determined from the study.