Total joint arthroplasties (TJAs) are increasing among the population; as a possible complication, prosthetic joint infections (PJIs) are gaining growing attention. While most common pathogens involved in PJI are Gram-positive bacteria, Salmonella spp. is a rare cause of PJI. Moreover, most cases of reported PJI caused by Salmonella spp. involve hip-arthroplasty rather than knee arthroplasty. For these reasons, indications for the best surgical and medical management of PJI involving knee-arthroplasties caused by Salmonella spp. are not clear. We report a case of knee-PJI caused by group D Salmonella in a 68-year-old woman from Romania, who was successfully treated with a two-stage revision surgery. Based on antimicrobial susceptibility of the cultural isolate, antibiotic therapy was administered between the two surgical stages and 4 weeks post-operatively. The patient was initially treated with trimethoprim/sulfamethoxazole 160mg/800mg per os tid; due to adverse effects, antimicrobial therapy was switched, after 15 days of treatment, to ertapenem 1g/day. At one year post-operatively, no sign or symptoms of relapse of the PJI were identified. The report of such rare but challenging cases shows that clinical success is achievable through appropriate medical and surgical management, which should be based on a strong collaboration between orthopedics and infectious disease specialists.