Background Fish is reported to be one of the most common causes of food allergic reactions. Species specificity and patterns of cross-reactivity are still to be defined. Objective To demonstrate the immunologic reactivity of clinically codfish-allergic adults to four species of fish: cod, mackerel, herring, and plaice. Methods IgE reactivity was measured in eight clinically codfish-allergic adult patients, confirmed by double-blind placebo-controlled challenges with fresh raw codfish, and in 30 codfish-tolerant control subjects, by means of skin prick test, histamine release test, specific IgE tests, SDS-PAGE, and immunoblotting. Results All eight patients had positive skin prick tests to plaice and herring, seven of eight to mackerel, whereas fish-induced histamine release from basophil leukocytes was positive in five, four, and six of six patients, respectively. Elevated specific IgE to the fish species was found in all eight, and reactions among the control subjects using an in-house method, the Maxisorp RAST, with freshly prepared fish extracts, were fewer (n = 8) than found with Phadebas RAST (n = 12) and Pharmacia CAP System (n = 11). Sodium dodecyl sulfate-polyacrylamide gel electrophoresis and immunoblotting revealed individual and common antigenic proteins in freshly prepared extracts. Sera from all eight patients recognized a protein in the area of 11 to 14 kD in all fish species. This is believed to be a protein fraction analogous to Gad cI. Inhibition of the codfish Maxisorp RAST was obtained with mackerel, herring, and plaice. No cross-reactivity to shrimp or milk was shown. Conclusion This study suggests that serologic cross-reactivity to different fish species in clinically codfish-allergic adults exists, and that cod, mackerel, herring, and plaice share a common antigenic structure.