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Purpose: Benzathine penicillin G (BPG) monthly administration is the most effective method for secondary prophylaxis against acute rheumatic fever (ARF). BPG’s efficacy largely depends on adherence to treatment. This study was aimed at assessing adherence toBPG prophylaxis and its determinants among adult patients with rheumatic heart disease. Patients and Methods: An institutional cross-sectional study design was used. One hundred and forty-five patients receiving monthly BPG at the Adult Cardiac Clinic ofTikur Anbessa Specialized Hospital (TASH) were interviewed. Their 1-year BPG prophylaxis administration record was also reviewed. The rate of adherence to BPG injection was determined by calculating the percentage of the administered drug from the total expected doses. Data were entered and analyzed using Statistical Package for Social Sciences (SPSS)software version 25. Both descriptive and logistic regression analyses were computed to describe different variables and assess factors associated with adherence, respectively. A p-value <0.05 was used to declare association.