Mycobacterium ulcerans inoculated into the footpads of mice at 6 x 10(3) CFU was shown to have a generation time of 6.5 days when estimated from weekly changes in microscopic counts of acid-fast bacilli (AFB) and 7.5 days when calculated from actual CFU enumerated on Lowenstein-Jensen egg medium incubated at 32 degrees C. Footpads became swollen at week 10 (W10) after infection, and all infected control mice were dead at W15 after infection. Daily (5 days/week) treatment with 100 mg of clarithromycin (CLR)/kg of body weight beginning the day after infection prevented swelling of footpads at W10. When initiation of treatment was delayed until obvious footpad swelling was observed, there was a reduction in both the increase in AFB counts and deterioration of swollen footpads and also a prolonged survival of the mice to W18. Mice infected in the hind footpads with 5 x 10(5) CFU of M. ulcerans were divided into an untreated control group and six treatment groups that received one of the following therapies for 8 weeks: 100 mg of CLR/kg, 25 mg of minocycline (MIN)/kg, 50 mg of sparfloxacin (SPX)/kg, 10 mg of rifampin (RIF)/kg, 10 mg of rifabutin (RBT)/kg, or 100 mg of amikacin (AMK)/kg. After completion of therapy, treated animals were observed for an additional 17 weeks. All control mice and mice treated with CLR, MIN, or SPX exhibited swollen footpads during the observation period. In contrast, of those animals treated with RIF, RBT, or AMK, none had footpad swelling and all inoculated cultures done after the W17 observation remained negative. These results suggest that RIF, RBT, and AMK may be effective in the treatment of human infection with M. ulcerans.