OBJECTIVES: In the treatment of prosthetic joint infections (PJI), the benefit of antibiotic therapy for more than 6 weeks after surgery is uncertain. We compared PJI cure rates according to the duration of antibiotics, 6 versus 12 weeks. METHODS: A prospective observational non-randomized study in Geneva University Hospitals 1996-2007. RESULTS: A total of 144 PJI (62 hip arthroplasties, 62 knee arthroplasties, and 20 hip hemiarthroplasties) were included with a prolonged follow-up ranging from 26 to 65 months. Surgical treatment included 60 debridements with implant retention, 10 one-stage exchanges of the prosthesis, 57 two-stage exchanges, and 17 Girdlestone procedures or knee arthrodeses. Seventy episodes (49%) received 6 weeks antibiotic therapy and 74 episodes, 12 weeks. Cure was achieved in 115 episodes (80%). Cure rate did not change according to the duration of intravenous antibiotics (>8 days, 8-21 days, >21 days) (Kruskal-Wallis-test; p = 0.37). In multivariate analysis, none of the following parameters was statistically significantly associated with cure: two-stage exchange (odds ratio 1.1,95%CI 0.2-4.8); number of debridements (0.9, 0.4-1.9); six weeks antibiotherapy (2.7, 0.96-8.3); duration of intravenous course (1.0, 0.96-1.03); sinus tract (0.6, 0.2-1.7); or MRSA infection (0.5, 0.2-1.5), although implant retention showed a tendency for less cure (0.3, 0.1-1.1). CONCLUSIONS: Following surgery for treatment of PJI, antibiotic therapy appears able to be limited to a 6-week course, with one week of intravenous administration. This approach needs confirmation in randomized trials.