Introduction |Shellfish allergy is an important cause of food allergies worldwide. Both in vivo and in vitro diagnostics failure nowadays is caused by the poor quality of the extracts associated with the scarce availability of allergenic molecules in the market. It is known that not all patients with shellfish allergies experience adverse reactions to mollusks. It is still unclear how to detect and diagnose correctly these patients. Aim |To investigate the features of shrimp-allergic patients either reactive or tolerant to mollusks, with the currently available diagnostic methods. Methods| Nineteen centers, scattered throughout Italy, participated in the study, enrolling patients allergic to shrimp with or without associated reactions to mollusks. Patients underwent skin tests using commercial extracts or fresh raw and cooked foods, and IgE reactivity to currently available allergenic extracts and molecules was measured in vitro. Results| Two hundred and forty-seven individuals with a history of adverse reaction to crustaceans participated in the study. Only 47.8% of them reacted after cephalopod or bivalve ingestion. None of the tests used, either in vivo or in vitro, was able to detect all selected patients. Accordingly, a great heterogeneity of results was observed with an agreement between in vivo and in vitro tests ranging between 52% and 62% of cases. Skin tests were able to identify the cephalopod and bivalve reactors (p <0.001), also using fresh cooked or raw food (p <0.001). The reactivity profile of mollusk reactors was dominated by Pen m 1, over Pen m 2 and Pen m 4 compared to the tolerant subjects, but 33% of patients allergic to shellfish were not detected by any of the available molecules. A higher frequency of shrimp hypersensitivity was recorded in northern Italy, while mollusk reactivity was more frequent in the center-south. Conclusion |The current diagnostic methods are inadequate to predict the cross-reactivity between crustaceans and mollusks. The detection of mollusks hypersensitivity must still rely on skin tests with fresh material. There is no need to exclude mollusks from shrimp allergic patients’ diet unless clinical history, the available diagnostic instruments, and/or tolerance tests support such a decision. Primary sensitization to mollusks seems possible.