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Background Penicillin allergy is the most frequent drug allergy, among which aminopenicillins are reputed for causing delayed rashes in children, particularly in the context of viral infections. Despite a negative allergy evaluation, a significant proportion of individuals continue to avoid penicillin antibiotics for fear of an allergic reaction. Objective To evaluate the safety and efficacy of a 5-day challenge to amoxicillin and the proportion of subsequent use of amoxicillin. Methods Pediatric patients with a history of a reaction to amoxicillin were prospectively recruited in the study. All patients were challenged, and those with negative immediate challenges underwent an ambulatory 5-day challenge to amoxicillin to rule out nonimmediate reactions. Patients were called 2 years after their initial allergy evaluation to assess subsequent amoxicillin use and tolerance. Results One hundred thirty children with a history of amoxicillin allergy underwent a graded drug provocation test (DPT) to amoxicillin. Three patients had a positive immediate challenge, 3 had a positive nonimmediate challenge, and 2 were equivocal. Of the 122 patients with a negative challenge, 114 (93.4%) were reached 2 years after their initial allergy evaluation: 75 had used antibiotics since, of which only 1 (1.3%) had refused to reuse amoxicillin because of fear of an allergic reaction. Finally, the 5-day DPT resulted in a 24.1% decrease in future penicillin avoidance compared with classical single-dose graded DPT performed for 1 day in a historical cohort (P Conclusion The 5-day challenge is a safe and effective way to rule out nonimmediate amoxicillin allergy, and it ensures better compliance with future penicillin use.