BACKGROUND: 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. OBJECTIVE: To assess the tolerability of meropenem in patients with documented penicillin allergy. DESIGN: Prospective skin testing and antibiotic challenge. SETTING: Allergy units of 2 Italian medical centers. PATIENTS: 104 consecutive participants with immediate hypersensitivity reactions to penicillins and positive skin test results to at least 1 penicillin reagent. MEASUREMENTS: Skin tests to meropenem and, if results were negative, challenges with escalating doses of meropenem. RESULTS: 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. LIMITATION: Challenges were not followed by therapeutic courses. CONCLUSIONS: 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.