Cefuroxime axetil has been shown to have efficacy comparable to doxycycline in adults with early Lyme disease (LD). Because of toxicity, doxycycline is usually avoided in children. For children who are unable to tolerate amoxicillin, there is currently no proven alternative oral therapy for LD. This randomized, unblinded study compared 2 dosage regimens of cefuroxime axetil (20 mg/kg/d and 30 mg/kg/d) with amoxicillin (50 mg/kg/d), each given for 20 days. Children were enrolled if they were 6 months to 12 years of age, had erythema migrans, and met other eligibility requirements. Serologic testing occurred at entry and after 6 months. Follow-up evaluations for safety, tolerability, and efficacy occurred at 10 and 20 days, 6 months, and 1 year. Forty-three children were randomized (13 in the amoxicillin group, 15 in each cefuroxime axetil group); 39 completed 12 months of follow-up. At the completion of treatment, there was total resolution of erythema migrans in 67% of the amoxicillin group, 92% of the low-dose cefuroxime group, and 87% of the high-dose cefuroxime group, and resolution of constitutional symptoms occurred in 100%, 69%, and 87%, respectively. All patients had a good outcome, with no long-term problems associated with LD. One patient, who was well at the first 2 follow-up visits, was treated with doxycycline because of new constitutional symptoms. Mild diarrhea occurred in a small number of participants in each group (1 patient was diagnosed and treated for Clostridium difficile-associated diarrhea, which occurred after completing the full course of study medication). No hypersensitivity reactions occurred. The number of patients in this trial was not sufficient to demonstrate a statistically significant difference between the 3 groups; however, both amoxicillin and cefuroxime axetil seem to be safe, efficacious treatments for children with early LD.