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Background β-lactams continue to remain the most commonly involved drug family in allergic drug reactions. They are often essential and there is a cost-effective and favourable risk-benefit ratio for the exploration of all suspicions of β-lactam allergy. A firm diagnosis is always based on skin tests and sometimes on provocation tests. Recommendations have been published by allergy societies and distinguished scientists but they are not always concordant and can lead to some confusion for the practicing allergologist. The situation has even worsened since the world wide withdrawal of these penicillin determinants and since the predominance of amoxicillin and cephalosporin prescriptions in most countries. Objective – Method In a recent article, it was stated that patients with a penicillin allergy history and negative skin tests to major and minor penicillin determinants are at a low risk of relapse (0–5%) when receiving a β-lactam. In this paper, our Drug Allergy and Hypersensitivity Database, a cohort database, was used to demonstrate that this statement is false. Standardized European Network for Drug Allergy questionnaires, skin test and challenge procedures were followed. Results One-thousand two-hundred and eighteen subjects, 69.8% of female, 51.7% of atopics, were included. 21.1% had a true β-lactam allergy confirmed by skin tests (178, 69.3%) or by drug provocation (79, 30.7%). 17.4% of the patients with negative skin tests to major and minor penicillin determinants were positive for a β-lactam. Conclusion In the diagnosis of β-lactams allergy, if all skin tests are negative, skin tests with other determinants and provocation tests under strict surveillance are mandatory. [ABSTRACT FROM AUTHOR]