Penicillins and cephalosporins are the most important betalactams inducing IgE-mediated reactions. The safety of administering cephalosporins to penicillin-allergic children is a particular problem, because cephalosporin allergenic determinants have not been properly identified. A study was undertaken to evaluate the frequency of anaphylactic reactions to cephalosporins and penicillins and their cross-reactivity in a pediatric population. A prospective survey was conducted in a group of 1170 children with suspected immediate allergic reactions to cephalosporins and/or penicillins, which were examined during a period of 8 yr. In vivo (skin tests and challenges) and in vitro tests (for specific IgE) were performed with standard concentration of penicillins and cephalosporins. When 1170 children with a clinical history of allergy to penicillins and/or cephalosporins were tested in vivo for immediate hypersensitivity to betalactams, 58.3% cases overall were found to be skin or challenge test positive. Among them, 94.4% patients were positive to penicillins and 35.3% to cephalosporins. The frequency of positive reactions in the in vivo testing was in the range from 36.4% to 88.1% for penicillins and from 0.3% to 29.2% for cephalosporins. However, 31.5% of the penicillin allergic children cross-reacted to some cephalosporin. If a child was allergic to a cephalosporin, the frequency of positive reactions to penicillin was 84.2%. The cross-reactivity between cephalosporins and penicillins varied between 0.3% and 23.9%. The cross-reactivity among different generations of cephalosporins varied between 0% and 68.8%, being the highest for first and second-generation cephalosporins and 0% for third generation cephalosporins. The frequency of immediate allergic reactions to cephalosporins is considerably lower compared to penicillins, and the degree of cross-reactivity between cephalosporins and penicillins depends on the generation of cephalosporins, being higher with earlier generation cephalosporins. The cross-reactivity among cephalosporins is lower compared to cross-reactivity between penicillins and cephalosporins.