Minocycline has demonstrated greater in vitro activity against anaerobic bacteria than its parent compound, tetracycline. In vivo therapeutic efficacy of the two drugs was tested against a mixed anaerobic infection in a mouse model. Fusobacterium necrophorum plus F. nucleatum injected intraperitoneally produced progressive intrahepatic and occasional extrahepatic abscesses, which were measured at autopsy. Three treatment regimens were tested, single daily doses of antibiotic being administered by oral gavage: four doses begun at 2 or 24 h after challenge and 14 doses begun 3 weeks after challenge when abscesses were well developed. Autopsy was not performed until several weeks after completion of treatment to assess long-term effects. Based on the number of mice without lesions, the median effective dose (ED(50)) in milligrams per kilogram per dose for minocycline was significantly lower than that for tetracycline with each regimen tested. With the 2-h (immediate therapy) regimen and the 24-h-delayed therapy regimen, minocycline was 30 and 6 times, respectively, more effective against hepatic abscesses than tetracycline on a weight basis. With each antibiotic, abscesses outside the liver were more resistant to therapy, although again minocycline was more effective. In the treatment of developed abscesses (3-week-delayed regimen), minocycline was effective (ED(50) <16 mg/kg), whereas tetracycline was ineffective (ED(50) >256 mg/kg). Minocycline has demonstrated greater therapeutic efficacy in vivo than tetracycline in this experimental infection, which is similar, in certain aspects, to human anaerobic infection. These data support further evaluation of the clinical usefulness of minocycline.