The specificity of pediatrician-diagnosed allergy reactions to penicillin, amoxicillin, and oral cephalosporins, which was based on contemporaneous examination of the patient, was evaluated by an elective skin testing program. Children and adolescents (n = 247) experiencing an adverse reaction to penicillin, amoxicillin, and/or an oral cephalosporin sufficient to lead to the recommendation to avoid further use were enrolled. Skin testing with penicillin G, commercial benzylpenicilloyl phosphate, penicillin minor determinate mixture, ampicillin, cefazolin, cefuroxime, and ceftriaxone was performed according to the suspected drug allergy followed by an oral challenge, repeat testing, and prospective follow-up if no reactions were observed. Overall, 84 (34.0%) of 247 patients had an IgE-type reaction on skin testing or oral challenge. Twenty-seven (32%) of 85 suspected penicillin reactions, 53 (34%) of 156 suspected amoxicillin reactions, and 13 (50%) of 26 suspected cephalosporin reactions were shown to be IgE mediated. Positive skin tests were observed in 20 patients with non-IgE-type clinical adverse reactions, including 15 patients with only a pruritic polymorphous rash. No reactions to oral challenge were severe after negative skin testing. One hundred sixty-three patients received multiple treatment courses with beta-lactam antibiotics after a negative skin testing procedure and three (1.8%) had adverse IgE reactions, all of which were mild. Physician-diagnosed allergic reactions to beta-lactam antibiotics based on patient examination at the time of the reaction is more accurate than patient history alone but still overestimates the rate of possible true allergy in 66% of patients. Elective penicillin, amoxicillin, and cephalosporin skin testing and oral challenge protocols are necessary to identify patients not at risk.