Methicillin-resistant Staphylococcus is a common cause of orthopaedic implant infections. In such cases, rifampicin is the antibiotic of choice, but it should not be administered alone to avoid the selection of resistant mutants. Linezolid has activity against resistant staphylococci and a high oral bioavailability; therefore, it could be a good option for combining with rifampicin. We describe 2 patients admitted to our hospital due to orthopaedic implant infections, who received combination therapy with linezolid and rifampicin. In both cases, the trough serum concentration of linezolid during rifampicin treatment was below the minimum inhibitory concentration required to inhibit the growth of 90% of organisms (MIC(90)) for staphylococci, but increased after rifampicin withdrawal. This finding suggests an interaction between rifampicin and linezolid, and a possible explanation is discussed.