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Background: Diabetic foot infection (DFI) is a common complication of hyperglycemia and is related to prolongation of hospitalization, mortality, high hospitalization costs and decreased quality of life. Antibiotic therapy is one of the most critical factors in the eradication of infection. This study aims to determine the appropriateness of antibiotic use based on the local and international clinical guidelines and its short-term effect on patients’ clinical improvement. Materials and Methods: This retrospective cohort study was conducted using secondary data from DFI inpatients from 1 January 2018 to 31 May 2020, from Dr. Cipto Mangunkusumo Hospital (RSCM), the National Referral Hospital of Indonesia. The Gyssens algorithm was used to help assess the appropriateness of antibiotics. All subjects were type 2 Diabetes Mellitus (T2DM) adult patients diagnosed with DFI. The primary outcome was a clinical improvement of infection after 7 - 14 days of antibiotic use. The clinical improvement of infection was defined by a minimum of three of these criteria: reduced or no purulent secretions, no fever, the area around the wound did not feel warm, no or reduced local oedema, no local pain, reduced redness or erythema, and decreased leukocytes count. Results: A total of 113 (63.5%) eligible subjects from a total of 178 were recruited. Among the patients, 51.4% had a duration of T2DM for ≥10 years, 60.2% had uncontrolled hyperglycemia, 94.7% had a history of complications, 22.1% had a history of amputation, and 72.6% had ulcer grade ≥3. Based on the Gyssens algorithm, 54.0% of the subjects were given antibiotics appropriately, while the other 46.0% were not. The proportion of improved patients in the appropriate antibiotics group was higher but not statistically significant than those in the inappropriate group (60.7% vs. 42.3%, P = 0.079). However, the results of the multivariate analysis demonstrated that the appropriate use of antibiotics would increase clinical improvement by 2.6 times, compared to inappropriate use after controlling for the covariates (adjusted odds ratio: 2.616, 95% confidence interval: 1.117 - 6.126, P = 0.027). Conclusion: Only half of the patients with DFI received appropriate antibiotics, although an appropriate antibiotics usage was independently associated with better short-term clinical improvement in DFI. This suggests that we should effort to improve appropriateness in antibiotics usage in DFI.