The optimal duration of antibiotic therapy for treating orthopaedic implant infections after surgical drainage and complete implant removal is unknown. This was a single-centre, unblinded, prospective trial randomizing (1:1) eligible patients to either 4 or 6 weeks of systemic, pathogen-targeted antibiotic therapy. We analysed 123 eligible patients (62 in the 4 week antibiotic arm and 61 in the 6 week arm) in the ITT analysis. The patients' median age was 64 years, 75 (61%) were men and 38 (31%) were immunocompromised. The most common types of infection treated included: two-stage exchange procedure for prosthetic joint infection (n"38); orthopaedic plate infection (44) and infected nail implants (11). The median duration of post-explant intravenous antibiotic therapy was 4 days. Overall, 120 episodes (98%) were cured microbiologically and 116 (94%) clinically after a median follow-up period of 2.2 years. During follow-up, four patients had a clinical recurrence with a pathogen other than the initial causative agent. We noted recurrence of clinical infection in four patients in the 4 week arm and three patients in the 6 week arm (4/62 versus 3/61; v2 test; P"0.74); in all cases, this occurred at around 2months following the end of antibiotic treatment. Conclusions: We found no statistically significant difference in the rates of clinical or microbiological remission between patients randomized to only 4 compared with 6 weeks of systemic antibiotic therapy after removal of an infected osteoarticular implant.