Abstract. Purpose: The purpose of this study was the clinical and therapeutic assessment of lower-limb osteosynthesis-associated infection (OAI) by multidrug-resistant (MDR) and extensively drug-resistant (XDR) Gram-negative bacteria (GNB), which have been poorly studied to date. Methods: A prospective multicentre observational study was conducted on behalf of ESGIAI (the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) Study Group on Implant-Associated Infections). Factors associated with remission of the infection were evaluated by multivariate and Cox regression analysis for a 24-month follow-up period. Results: Patients (n=57) had a history of trauma (87.7 %), tumour resection (7 %) and other bone lesions (5.3 %). Pathogens included Escherichia coli (n=16), Pseudomonas aeruginosa (n=14; XDR 50 %), Klebsiella spp. (n=7), Enterobacter spp. (n=9), Acinetobacter spp. (n=5), Proteus mirabilis (n=3), Serratia marcescens (n=2) and Stenotrophomonas maltophilia (n=1). The prevalence of ESBL (extended-spectrum β-lactamase), fluoroquinolone and carbapenem resistance were 71.9 %, 59.6 % and 17.5 % respectively. Most patients (n=37; 64.9 %) were treated with a combination including carbapenems (n=32) and colistin (n=11) for a mean of 63.3 d. Implant retention with debridement occurred in early OAI (66.7 %), whereas the infected device was removed in late OAI (70.4 %) (p=0.008). OAI remission was achieved in 29 cases (50.9 %). The type of surgery, antimicrobial resistance and duration of treatment did not significantly influence the outcome. Independent predictors of the failure to eradicate OAI were age >60 years (hazard ratio, HR, of 3.875; 95 % confidence interval, CI95 %, of 1.540–9.752; p=0.004) and multiple surgeries for OAI (HR of 2.822; CI95 % of 1.144–6.963; p=0.024). Conclusions: Only half of the MDR/XDR GNB OAI cases treated by antimicrobials and surgery had a successful outcome. Advanced age and multiple surgeries hampered the eradication of OAI. Optimal therapeutic options remain a challenge.