Background: Rheumatic heart disease (RHD) continues to create havoc in the developing countries even decades after its discovery. It is entirely preventable through primordial, primary, and secondary level intervention. Secondary prevention is a reasonable treatment option in patients in India, but it suffers due to poor adherence which remains the main impediment to its implementation. The aim is to study the compliance with benzathine penicillin as secondary prophylaxis in RHD patients and to establish the patient-related factors for adherence and reasons for missing of doses. Materials and Methods: This is a cross-sectional study of RHD patients presenting to our institute. The demographic data, clinical history, and details of penicillin prophylaxis were noted. The patient was labeled as compliant or noncompliant depending on frequency and duration of prophylaxis as prescribed. Potential factors between the two groups have been analyzed by univariate and binary logistic regression. Results: The study cohort of 500 patients consisted of 261 compliant and 239 noncompliant patients. Average age of presentation was 29 ± 13 years with females outnumbering the males. Noncompliance with secondary prophylaxis was more prevalent among male (P = 0.003), low socioeconomic class (P = 0.0009), uneducated (P = 0.000018), and the rural population (P = 0.025) while those with previous history of rheumatic fever (RF) were found to be more compliant (P = 0.04). Recurrences of RF were more common in those not on regular prophylaxis (P = 0.011). The most common reason cited for noncompliance was the absence of proper counseling followed by a sense of well-being, injection site pain and financial constraints. Conclusion: Compliance with secondary penicillin prophylaxis is essential to ensure eradication of RHD. Education about the importance and necessity of prophylaxis would improve compliance. A close patient and health personnel relationship is important in improving adherence to secondary prophylaxis.