The treatment of rheumatoid arthritis (RA) has recently seen a paradigm shift with the introduction of biologic therapy, but there is concern that this will result in an increased incidence of infection. The occurrence of infection in RA patients who have undergone biologic therapy has recently been documented in a few reports, but this is the first report of Salmonella infection after total knee arthroplasty (TKA) in a RA patient receiving etanercept therapy. Here we report the successful treatment of a rare case of Salmonella septic arthritis. A 61-year-old man with a 4-year history of RA was treated with methylprednisolone and methotrexate, and he consulted us because of right gonalgia. Treatment with infliximab was started, but as this was not effective, his medication was changed sequentially to etanercept 6 months later. Finally, TKA was performed on the right knee with antibiotic-loaded acryl cement (ALAC). The postoperative course was uneventful, etanercept was administered routinely from the 2nd postoperative week. The patient was discharged after 4 weeks. Five weeks after TKA, however, the patient visited us because of acute swelling and tenderness around the right knee. His laboratory values included a white blood cell count of 9300/mm3, an erythrocyte sedimentation rate of 81.0 mm/h and a C-reactive protein level of 11.3 mg/dl. Fluid obtained by joint aspiration was cloudy and dark-yellow, and prosthetic joint infection was diagnosed. The patient underwent emergency debridement by arthroscopic surgery, followed immediately by injection of 0.5 g carbapenem every 12 hours and continuous closed irrigation-suction of the joint for 2 weeks. Culture of the joint fluid revealed Salmonella enteritidis infection, which was not sensitive to aminoglycoside which we used as ALAC. The patient was treated with intravenous carbapenem for 3 weeks, oral levofloxacin at a daily dose of 300 mg for 2 weeks successively, and oral minocycline at 200 mg daily for 3 months. At follow-up 12 months after surgery, physical and blood examinations and plain radiographs demonstrated no recurrence of the infection, and the patient has resumed taking etanercept. The range of flexion in the treated knee is 0 to 145 degrees. Salmonella arthritis is classified as septic arthritis and reactive arthritis, and septic arthritis is more likely if Salmonella is identified by culture of joint fluid. Salmonella septic arthritis has not been considered an intraoperative contaminant during joint replacement. Recently, it has become apparent that biologic therapies can play major roles in the pathogenesis of RA, and also that immuno-suppressive drugs may become risk factors for Salmonella septic arthritis. In conclusion, our patient had a successful outcome after prompt debridement and treatment with appropriate antibiotics, without the need for implant removal. It is important to be mindful of the possibility of infection and to carry out surgery immediately if a patient presents with symptoms after biologic therapy.