Antibiotic treatment of native osteomyelitis caused by extended-spectrum β-lactamase-producing Enterobacterales (ESBL-PE) is a challenge. Limited epidemiological and outcome data are available. This retrospective cohort study included osteomyelitis patients with ESBL-PE infections treated in a reference centre for bone and joint infections (BJIs) between 2011-2019. Twenty-nine patients with native BJI (mean age, 44.4 ± 15.7 years) were analysed. Fifteen cases were paraplegic patients with ischial pressure sores breaching the hip capsule. Other cases included eight other hip infections, four tibial infections and two foot infections. Infections were mostly polymicrobial (n=23; 79.3%), including Staphylococcus aureus (n=13; 8 methicillin-resistant). Klebsiella pneumoniae (n=13) was the most frequent ESBL-producing species identified, followed by Escherichia coli (n=10), including 3 E. coli/K. pneumoniae co-infections, and Enterobacter spp. (n=9). ESBL-PE were rarely susceptible to fluoroquinolones (n=4; 13.8%). Most therapies were based on carbapenems (n=22) and combination therapies (n=19). The median duration of treatment was 41 (5-60) days. Primary control of the infection was achieved in 62.1% (18/29) of cases and up to 86.2% after second look surgeries, after a median follow-up of 6 (1-36) months. Infection with ESBL-producing K. pneumoniae was associated with failure (P=0.001), whereas age, infection location, prior colonisation and antimicrobial therapy were not found to be predictors of outcome. ESBL-PE native BJIs are often polymicrobial and fluoroquinolone-resistant infections caused by K. pneumoniae, highlighting the need for expert centres with pluridisciplinary meetings with experienced surgeons.