Background: Rheumatic heart disease (RHD) is one of the major causes of cardiovascular rndisease in developing countries, affecting most of the young population. Secondary prophylaxisrnin the form of benzathine penicillin is effective for preventing recurrent acute rheumatic feverrn(ARF) and the progression of RHD. However, the low adherence rate reduced the effectiveness.rnTherefore, a systematic generalizable tool is necessary to tackle the barriers. rnObjective: The purpose of the study was to assess adherence and barriers to use secondaryrnprophylaxis for RHD, at Tikur Anbessa specialized hospital (TASH). rnMethods: Cross-sectional study was conducted from June 5, 2020, to September 4, 2020, atrnTikur Anbessa Specialized Hospital, Ethiopia. A structured questioner was used for the data rncollection on awareness, adherence, and barriers for benzathine penicillin prophylaxis in adultsrnwith RHD. Data were analyzed using SPSS version 26. rnResults: A total of 385 patients participated in this study, 305(79.6%) patients were aware, sorernthroat associated with heart disease, and about 288 (75.6%) patients; know that benzathine rnpenicillin prevents tonsillitis. The adherence rate was 77.9% for benzathine penicillinrnprophylaxis (BPG) while the left 85 patients (22.1%) were non-adhered to the prophylaxis. Thernmain barriers for none adherence in this study were the nonavailability of medication, forgetting,rnand health professionals refuse to inject benzathine penicillin. Increased age was found to have arnsignificant association with adherence to BPG. For each one-year increase in the age of patientsrnwith RHD, the percent odds of adherence decreases by 3% (P value 0.006) rnConclusion: Adherence level was low, which is below WHO recommendation. This studyrninsight important major barriers that affect secondary prophylaxis for RHD that can be used to rndevelop an intervention to improve adherence.