The aim of this study is to describe our experience with linezolid plus rifampin as a salvage therapy in prosthetic joint infections (PJIs) when other antibiotic regimens failed or were not tolerated. A total of 161 patients with a documented prosthetic joint infection were diagnosed with a PJI and prospectively followed up from January 2000 to April 2007. Clinical characteristics, inflammatory markers, microbiological and radiological data, and antibiotic treatment were recorded. After a 2-year follow-up, patients were classified as cured when the prosthesis was not removed, symptoms of infection disappeared, and inflammatory parameters were within the normal range. Any other outcome was considered a failure. The mean age of the entire cohort (n = 161) was 67 years. Ninety-five episodes were on a knee prosthesis (59%), and 66 were on a hip prosthesis (41%). A total of 49 patients received linezolid plus rifampin: 45 due to failure of the previous antibiotic regimen and 4 due to an adverse event associated with the prior antibiotics. In no case was the implant removed. The mean (standard deviation) duration of treatment was 80.2 (29.7) days. The success rate after 24 months of follow-up was 69.4% (34/49 patients). Three patients developed thrombocytopenia and 3 developed anemia; however, it was not necessary to stop linezolid. Linezolid plus rifampin is an alternative salvage therapy when the implant is not removed.