Therapy with vancomycin alone or ciprofloxacin alone did not significantly reduce the number of methicillin-resistant Staphylococcus aureus (MRSA) in bone in rats with experimental osteomyelitis, compared with the number in control rats. Treatment with rifampin significantly (p less than 0.01) decreased the number of MRSA per gram of bone compared with the number in control animals. There was no significant difference in the results of therapy with rifampin compared with the results obtained with the combination of vancomycin plus rifampin. The combination of ciprofloxacin plus rifampin was the most effective regimen for the treatment of MRSA experimental osteomyelitis and the results of therapy were significantly (p less than 0.01) superior to those following treatment with rifampin alone or the combination of vancomycin and rifampin. Following cessation of antimicrobial therapy, significant (p less than 0.01) regrowth of MRSA in bone occurred in animals treated with rifampin alone or ciprofloxacin plus rifampin. The emergence of resistance of MRSA during treatment occurred in two rats treated with rifampin alone and in one treated with rifampin plus vancomycin.