Abstract Background The optimal duration and choice of antibiotic for fracture-related infection (FRI) is not well-defined. This study aimed to determine whether antibiotic duration (≤6 weeks versus >6 weeks) is associated with infection-free and surgery-free survival. The secondary aim was to ascertain risk factors associated with surgery- and infection-free survival. Methods We performed a multicenter, retrospective study of patients diagnosed with FRI between 2013 and 2022. The association between antibiotic duration and surgery-free and infection-free survival was assessed using Cox proportional hazard models. Models were weighted by the inverse of the propensity score, calculated using a priori variables of hardware removal; infection due to; Staphylococcus aureus, Staphylococcus lugdunensis, Pseudomonas or Candida species; and flap coverage. Multivariable Cox proportional hazard models were run with additional covariates including initial pathogen, need for flap, and hardware removal. Results Of 96 patients, 54 (56.3%) received ≤6 weeks and 42 (43.7%) received >6 weeks of antibiotics. There was no association between longer antibiotic duration and surgery-free survival (HR: 0.95; 95% CI: 0.65-1.38; p = 0.78) or infection-free survival (HR: 0.77; 95% CI: 0.30-1.96; p = 0.58). Negative culture was associated with increased hazard of reoperation or death (HR: 3.52; 95% CI: 1.99-6.20; p < 0.001) and reinfection or death (HR: 3.71; 95% CI: 1.24-11.09; p < 0.001). Need for flap coverage had an increased hazard of reoperation or death (HR: 3.24; 95% CI: 1.61-6.54; p = 0.001). Conclusions The ideal duration of antibiotics to treat FRI is unclear. In this multicenter study there was no association between antibiotic treatment duration and surgery-free or infection-free survival.