The chief focus of secondary prevention is antibiotic prophylaxis. This comprises long-term antibiotic therapy for individuals with acute rheumatic fever (ARF) or rheumatic heart disease (RHD), to prevent ARF recurrences triggered by recurrent group A streptococcal infections, and thereby prevent development or worsening of RHD. Standard recommendations include use of intramuscular benzathine penicillin G at least every 28 days for a minimum 5–10-years period after diagnosis of ARF. Challenges include the following: programmatic delivery of this regimen, which requires effective recall systems and use of pain-minimizing techniques for injection delivery; the need for culturally and age-appropriate adherence support tailored for young people; penicillin intolerance (which is uncommon); and securing the penicillin supply, especially in low-income settings.