INTRODUCTION: Fracture-related infection (FRI) represents a challenging clinical scenario. Limited evidence exists regarding treatment failure after initial management of FRI. The objective of our investigation was to determine incidence and risk factors for treatment failure in FRI. MATERIALS AND METHODS: We conducted a retrospective review of patients treated for FRI between 2011 and 2015 at three level 1 trauma centers. One hundred and thirty-four patients treated for FRI were identified. Demographic and clinical variables were extracted from the medical record. Treatment failure was defined as the need for repeat debridement or surgical revision seven or more days after the presumed final procedure for infection treatment. Univariate comparisons were conducted between patients who experienced treatment failure and those who did not. Multivariable logistic regression was conducted to identify independent associations with treatment failure. RESULTS: Of the 134 FRI patients, 51 (38.1%) experienced treatment failure. Patients who failed were more likely to have had an open injury (31% versus 17%; p = 0.05), to have undergone implant removal (p = 0.03), and additional index I&D procedures (3.3 versus 1.6; p < 0.001). Most culture results identified a single organism (62%), while 15% were culture negative. Treatment failure was more common in culture-negative infections (p = 0.08). Methicillin-resistant Staphylococcus aureus (MRSA) was the most common organism associated with treatment failure (29%; p = 0.08). Multivariate regression demonstrated a statistically significant association between treatment failure and two or more irrigation and debridement (I&D) procedures (OR 13.22, 95% CI 4.77-36.62, p < 0.001) and culture-negative infection (OR 4.74, 95% CI 1.26-17.83, p = 0.02). CONCLUSIONS: The rate of treatment failure following FRI continues to be high. Important risk factors associated with treatment failure include open fracture, implant removal, and multiple I&D procedures. While MRSA remains common, culture-negative infection represents a novel risk factor for failure, suggesting aggressive treatment of clinically diagnosed cases remains critical even without positive culture data. LEVEL OF EVIDENCE: Retrospective cohort study; Level III.