Background: Diagnosing immediate hypersensitivity to β-lactam antibiotics is still a significant problem. Recently, a new penicillin testing reagent was introduced to the market. In this study, the recommendations of the European Network of Drug Allergy (ENDA) for the diagnosis of immediate reactions to β-lactams were followed, and the negative predictive value of this approach with currently available reagents was assessed. Methods: Eighty patients (age range: 6–74 years) with a history of immediate reactions to β-lactams were included. All cases underwent skin testing with benzylpenicilloyl-polylysine (PPL) and minor determinant mixture (MDM), followed by the culprit drug if necessary. If this step was negative, a drug provocation test was offered. If this step also yielded a negative result, then the patients were recommended to use β-lactam antibiotics in future whenever their use was indicated. Results: Overall, 29 patients (36.2%) were diagnosed as β-lactam allergic. The majority of the cases (72.4%) were diagnosed by positive skin tests to either PPL or MDM, whereas 10.3% were diagnosed by skin testing with culprit drugs and 17.2% with drug provocation tests. Regarding the use of the tested drug in the long term, almost half of the contacted patients had had an indication to use the tested drug and the majority had taken the whole course without problems. Conclusions: Although currently available new penicillin tests provide sufficient allergy data, all the steps recommended by ENDA should be followed in the diagnosis of immediate reactions to β-lactams. If these steps are negative, the patients usually tolerate β-lactams and only a few develop mild, non-life-threatening reactions in the long term.