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Objective To assess the prevalence of discontinuation of short-term oral antibiotic therapy and to identify its predictors among patients attending outpatient department pharmacy units of public hospitals in Harar, Eastern Ethiopia.Design Facility-based prospective follow-up study.Setting All public hospitals in Harar, Eastern Ethiopia.Participants A total of 422 patients who received short-term oral antibiotics from Hiwot Fana Comprehensive Specialized Hospital (HFCSH) and Jugal General Hospital (JGH) from 20 January to 20 April 2024 were recruited using a systematic random sampling technique. Of the participants enrolled during the initial recruitment, only 400 completed the follow-up interview and were therefore included in the final analysis. The mean age of the respondents was 35.89±13.21 years and 280 (70.0%) were female.Primary and secondary outcome measures The primary outcome was discontinuation of short-term oral antibiotic therapy, measured based on self-reported leftover antibiotics. Multivariable logistic regression was used to identify factors associated with discontinuation. Adjusted ORs (AORs) with 95% Confidence Intervals (CIs) were reported, and statistical significance was set at p<0.05.Results The prevalence of short-term oral antibiotic discontinuation was 35.3% (95% CI 31% to 40%). Factors independently associated with antibiotic discontinuation included larger family size (AOR=1.18; 95% CI 1.01 to 1.36), a negative attitude towards antibiotics (AOR=2.09; 95% CI 1.19 to 3.66), dissatisfaction with medication-related information (AOR=7.20; 95% CI 2.84 to 18.24), prescriptions for dental indications (AOR=7.50; 95% CI 2.21 to 25.50), treatment duration of ≥7 days (AOR=2.88; 95% CI 1.08 to 7.68) and interruption of therapy during the treatment course (AOR=4.06; 95% CI 2.14 to 7.33).Conclusions Short-term oral antibiotic discontinuation remains a substantial challenge among outpatients, highlighting important gaps in adherence and continuity of care. Patient perceptions, the adequacy of medication counselling and treatment-related characteristics appear to play a critical role in shaping adherence behaviour. Targeted interventions to improve patient education, communication and follow-up support are essential to promote appropriate antibiotic use and help reduce the risk of antimicrobial resistance.