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Although clinicians avoid giving meropenem to patients with penicillin allergy because of potential cross-reactivity, the rate of cross-reactivity between penicillins and meropenem has not been prospectively determined.To assess the tolerability of meropenem in patients with documented penicillin allergy.Prospective skin testing and antibiotic challenge.Allergy units of 2 Italian medical centers.104 consecutive participants with immediate hypersensitivity reactions to penicillins and positive skin test results to at least 1 penicillin reagent.Skin tests to meropenem and, if results were negative, challenges with escalating doses of meropenem.One participant (0.9% [95% CI, 0.02% to 5.2%]) had a positive intradermal test result to meropenem. The remaining 103 participants with negative skin test results to meropenem tolerated escalating dose challenges.Challenges were not followed by therapeutic courses.These data indicate a low rate of cross-reactivity between penicillins and meropenem. Therefore, the practice of avoiding meropenem therapy in penicillin-allergic patients should be reconsidered. In patients who especially require meropenem treatment, the authors recommend pretreatment skin tests because negative results indicate tolerability.