In recent years, patients allergic to amoxicillin (AX) but with good tolerance of penicillin G (PG) have been described. It has been suggested that the epitope implicated in this type of sensitization might be located on the side-chain of the AX molecule. Thus, cross-reactivity between AX and cephadroxil (CEPH), a cephalosporin which shares an identical side-chain with AX, is suspected. This study aimed to demonstrate clinical cross-reactivity between AX and CEPH in patients allergic to AX and showing good tolerance of PG. In 76 of 576 subjects with suspected allergic reaction to PG and/or AX, the diagnosis of allergy was confirmed. All of these had specific IgE to PG, penicillin V, or AX, and/or positive skin tests to PPL (penicilloyl-polylysine), or MDM (minor determinant mixture), or PG, or AX, and/or positive challenge tests with PG and/or AX. Sixteen subjects (21%) allergic to AX (11 with positive skin test and five with positive challenge test to AX) and good tolerance of PG (all with negative parenteral challenge test) were selected. These 16 patients were subsequently challenged with CEPH (up to 500 mg). Fourteen patients tolerated CEPH, and two (12%) had an immediate allergic reaction. Our study indicates that allergy to the side-chain of aminopenicillins seems to have little clinical relevance in patients with allergic reactions to aminopenicillins but with good tolerance of PG, as 88% of patients with this clinical characteristic tolerate a cephalosporin which shares an identical side-chain. It seems that IgE from most of these patients recognizes an epitope different from the side-chain and the beta-lactam ring.