OBJECTIVES: To discuss the amoxicillin use as an alternative to penicillin and compare its cost for antibiotic prophylaxis in children with SCD.  METHODS: We searched for evidences in MEDLINE (Pubmed) with the terms "Anemia, Sickle Cell"[Mesh] and "Antibiotic Prophylaxis"[Mesh]. In a deterministic fashion, adopting the Brazilian public health system perspective, we did a budget impact analysis comparing amoxicillin to penicillin. The target population was estimated from hidroxyurea consumption in children with SCD and acquisition costs, both obtained from Ministry of Health databases (2012 values; exchange rate: US$ 1 = R$ 2.04). Data about dosage according to age and bodyweight were extracted from literature. RESULTS: A systematic review supports the use of penicillin prophylaxis in children with SCD, based on 3 RCTs (OR: 0.37; CI 95%: 0.16 to 0.86), with no results for amoxicillin. Although, prospective studies show a low compliance of this approach (40 to 60%). Comparisons of amoxicillin to penicillin in other settings, as rheumatic fever prevention, demonstrate that once-daily oral amoxicillin is not inferior to twice-daily penicillin. We estimated a range of 143 to 325 children, less than 5 years old, with SCD as our target population. Assuming oral daily doses of 1500 mg (or 750 mg if bodyweight less than 30 kg) for amoxicillin and 500 mg (or 250 mg if bodyweight less than 20 kg) for penicillin, the annual acquisition costs of penicillin, oral solution, to treat this population can lead to expenses of US$ 41,161.93 to US$ 93,704.65. In contrast, expenses with amoxicillin, oral solution, would be a range of US$ 3,019.94 to US$ 6,863.49.  CONCLUSIONS: As well as penicillin, amoxicillin seems to be a good option for preventing pneumococcal infection in children with SCD as its use could represent annual savings of US$ 38,141.99 to US$ 86,841.15 and the once-daily administration could improve the prophylaxis compliance.