Background: Rheumatic heart disease is a preventable cardiovascular disease that affects over forty million people worldwide. Poor adherence to secondary prophylaxis increases the risk of recurrent acute rheumatic fever. Studies on adherence to secondary prophylaxis in Ethiopia are scarce. Thus, this study aimed to determine adherence to secondary prophylaxis and risk factors among patients with rheumatic heart disease. Methods: Facility-based cross-sectional study design was employed to conduct this study from December 25/2021 to January 22/ 2022. The study was performed among rheumatic heart disease patients in randomly selected four public hospitals in Addis Ababa. Data were collected through face-to-face interviews using a structured questionnaire from follow-up patients after using a pre-tested questionnaire. Data were entered into EPI info version 7.2 and exported to SPSS version 26 for analysis. Multivariable logistic regression analysis was performed using variables with a p-value of less than 0.25 in bi-variable logistic regression analysis. Adjusted Odds Ratio (AOR) with a 95% confidence interval was estimated to determine the strength of association with poor adherence. Statistical significance multivariable logistic regression analysis was declared when the p-value is <0.05. Results: Three hundred and eighty-one study participants completed the study with a response rate of 95%. The mean age of the respondents was 26.45 ±10.5 years.