The purpose of this prospective clinical study is to evaluate the role of combination chemotherapy with rifampin in the treatment of orthopedic device-related infections in which the implant could not be removed. Eleven patients with orthopedic implant-related infections due to staphylococci or streptococci were treated with the implant in situ. Each antimicrobial regimen included rifampin in combination with a beta-lactam antibiotic or ciprofloxacin. The median duration of treatment with rifampin was 86 days (range, 15-336 days) with a median follow-up of greater than 24 months after cessation of therapy. Treatment was successful for 82% of patients. Failures were associated with documented inappropriate treatment. These preliminary clinical data are supported by data from in vitro studies and animal experiments. Combination therapy with rifampin, in particular rifampin and a quinolone, should be considered for patients with orthopedic implant-related infections if the implant cannot be removed.