Scope Despite a sequence homology of 90% between bovine and caprine beta-caseins (CN), IgE antibodies from patients allergic to goat's milk (GM), but tolerant to cow's milk (CM), recognize caprine beta-CN without cross-reacting with bovine beta-CN. We investigated this lack of cross-reactivity by evaluating the IgE-reactivity toward peptides isolated from plasmin hydolysates of bovine and caprine beta-CN. Methods and results The IgE-binding capacity of plasmin-derived peptides was evaluated with sera from 10 CM-allergic patients and 12 GM-allergic/CM-tolerant patients. In CM-allergic patients, IgE reactivity of caprine fragments (f29-107) and (f108-207), but not (f1-28), was similar to that of the bovine counterparts. In contrast, all bovine fragments were poorly recognized by IgE antibodies from GM-allergic/CM-tolerant patients. The peptide (f29-107) was generally the most immunoreactive fragment of caprine beta-CN. By using synthetic peptides, the immunodominant IgE-binding epitope recognized by most GM-allergic/CM-tolerant patients was located in the caprine domain 4979. Conclusion The restricted specificity of the IgE response toward the caprine beta-CN in GM-allergic/CM-tolerant patients is mainly directed against the domain 4979, which differs from its bovine counterpart by only three amino acid substitutions.