question: AIM: To investigate the rate of antibiotic resistance and its main risk factors in a population of patients with diabetic foot infection (DFI) during the COVID-19 pandemic, in comparison with the population of 2019. METHODS: Two hundred and twenty-five patients with DFI were admitted in a tertiary care center from January 2019 to December 2020. Antibiotic resistance was evaluated by microbiological examination of soft tissues' or bone's biopsy. RESULTS: Compared with 2019 group (n = 105), 2020 group (n = 120) had a significantly higher prevalence of antibiotic resistance [2019 vs 2020, 36% vs 63%, P <0.001] and more often was admitted with recent or current antibiotic therapy (18% vs 52%, P <0.001), which was frequently self-administered (5% vs 30%, P = 0.032). The risk of antibiotic resistance was also higher in 2020 group [OR 95% CI, 2.90 (1.68 to 4.99)]. Prior hospitalization, antibiotic self-administration and antibiotic prescription by general practitioners resulted as independent predictors of antibiotic resistance. CONCLUSIONS: In a population of people with DFI admitted in a tertiary care center during the COVID-19 pandemic the prevalence of antibiotic resistance was higher than 2019. Previous hospitalization, antibiotic self-administration /prescription by general practitioners were related to higher risk of antibiotic resistant infections.