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Background Data are limited about the value of skin tests in the diagnosis of proton pump inhibitor ( PPI)-induced hypersensitivity reactions and the cross-reactivity between PPIs. We aimed to assess the role of skin testing in the diagnosis of PPI-related immediate hypersensitivity reactions and the cross-reactivity patterns among PPIs. Methods The study was designed in a prospective, national, multicentre nature. Sixty-five patients with a suggestive history of a PPI-induced immediate hypersensitivity reaction and 30 control subjects were included. Standardized skin prick and intradermal tests were carried out with a panel of PPIs. Single-blind, placebo-controlled oral provocation tests ( OPTs) with the PPIs other than the culprit PPI that displayed negative results in skin tests ( n = 61) and diagnostic OPTs with the suspected PPI ( n = 12) were performed. Results The suspected PPIs were lansoprazole ( n = 52), esomeprazole ( n = 11), pantoprazole ( n = 9), rabeprazole ( n = 2), and omeprazole ( n = 1). The sensitivity, specificity, and negative and positive predictive values of the skin tests with PPIs were 58.8%, 100%, 70.8%, and 100%, respectively. Fifteen of the 31 patients with a hypersensitivity reaction to lansoprazole had a positive OPT or skin test result with at least one of the alternative PPIs (8/52 pantoprazole, 6/52 omeprazole, 5/52 esomeprazole, 3/52 rabeprazole). Conclusion Considering the high specificity, skin testing seems to be a useful method for the diagnosis of immediate-type hypersensitivity reactions to PPIs and for the evaluation of cross-reactivity among PPIs. However, OPT should be performed in case of negativity on skin tests. [ABSTRACT FROM AUTHOR]