Background-Acute rheumatic fever and subsequent rheumatic heart disease remain significant in developing countries. We describe a cost-effective analysis of 7 strategies for the primary prevention of acute rheumatic fever and rheumatic heart disease in children presenting with pharyngitis in urban primary care clinics in South Africa. Methods and Results-We used a Markov model to assess the cost-effectiveness of treatment with intramuscular penicillin using each of the following strategies: (1)

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... empirical (treat all); (2) positive throat culture (culture all); (3) clinical decision rule (CDR) score ≥2 (CDR 2+); (4) CDR score ≥3 (CDR 3+); (5) treating those with a CDR score ≥2 plus those with CDR score <2 and positive cultures (CDR 2+, culture CDR negatives); (6) treating those with a CDR score ≥3 plus those with CDR score <3 and positive cultures (CDR 3+, culture CDR negatives); and (7) treat none. The strategies ranked in order from lowest cost were treat all ($11.19 per child), CDR 2+ ($11.20); the CDR 3+ ($13.00); CDR 2+, culture CDR negatives ($16.42); CDR 3+, culture CDR negatives ($23.89); and culture all ($27.21). The CDR 2+ is the preferred strategy at less than $150/quality-adjusted life year compared with the treat all strategy. A strategy of culturing all children compared with the CDR 2+ strategy costs more than $125 000/quality-adjusted life year gained. Conclusions-Treating all children presenting with pharyngitis in urban primary care clinics in South Africa with intramuscular penicillin is the least costly. A strategy of using a clinical decision rule without culturing is overall the preferred strategy. A strategy of culturing all children may be prohibitively expensive. (Circ Cardiovasc Qual Outcomes. 2013;6:343-351.)