Background: True allergy to penicillin is rare, despite the high frequency with which it is reported. While most patients reporting penicillin allergy are not prone to anaphylaxis, it is not currently known what percentage of these patients will tolerate dose challenges of penicillin-based antibiotics. This review aims to determine the rate of tolerance in patients reporting penicillin allergy when challenged with penicillin-based antibiotics., Methods: We searched MedLine, Embase, and Cochrane Library for publications with English language translations between the years 2000 and 2017. We included randomized controlled trials, quasi-experimental, and observational studies of participants reporting penicillin allergy who received at least one systemic dose of a penicillin in the form of a drug challenge. At least 2 independent reviewers extracted data from included studies and assessed the quality of each included study. To generate primary outcome data, we calculated a summary estimate rate of penicillin tolerance from a pooled proportion of participants receiving penicillin with no adverse effects., Results: Initial literature search yielded 2945 studies, of which 23 studies were ultimately included in our review; 5056 study participants with reported history of penicillin allergy were challenged with a penicillin. After weighting for study sample size, a pooled average of 94.4% (95% confidence interval, 93.7%-95%) of participants tolerated the dose challenge without any adverse reaction., Conclusion: Misrepresented penicillin allergy drives unnecessary use of alternative antibiotics, which may be less effective, more toxic, and more expensive than using penicillin. In addressing the problem of penicillin allergy over-diagnosis, evaluation should go beyond risk for type 1 hypersensitivity. Our data suggest that 94.4% of 5056 participants with reported penicillin allergy determined to be clinically appropriate for allergy evaluation tolerated repeat administration of penicillin-based antibiotics without any adverse reactions. This review generates meaningful information useful to clinical predictive analytics, in evaluating and managing patients with a reported history of penicillin allergy., (Copyright © 2019 Elsevier Inc. All rights reserved.)