BACKGROUND: There is no recent systematic review on therisk of cross-reactivity to cephalosporins and carbapenems inpenicillin-allergic patients despite many new studies on the subject. All past reviews have several limitations such as not including any patient with a T-celle mediated penicillin allergy. OBJECTIVES: To determine the risk of cross-reactivity to cephalosporins and carbapenems in patients with a proven IgE-or T-cellemediated penicillin allergy. To measure the association between R1 side chain similarity on cephalosporins andpenicillins and the risk of cross-reactivity. METHODS: MEDLINE and EMBASE were searched fromJanuary 1980 to March 2019. Studies had to include at least 10 penicillin-allergic subjects whose allergy had been confirmed bya positive skin test (ST) or drug provocation test (DPT) result.Cross-reactivity had to be assessed to at least 1 cephalosporin orcarbapenem through ST or DPT. Both random-effects andfixed-effect models were used to combine data. A bioinformaticmodel was used to quantify the similarity between R1 sidechains. RESULTS: Twenty-one observational studies on cephalosporincross-reactivity involving 1269 penicillin-allergic patientsshowed that the risk of cross-reactivity varied with the degree ofsimilarity between R1 side chains: 16.45% (95% CI, 11.07-23.75) for aminocephalosporins, which share an identical sidechain with a penicillin (similarity score[1), 5.60% (95% CI,3.46-8.95) for a few cephalosporins with an intermediate simi-larity score (range, 0.563-0.714), and 2.11% (95% CI, 0.98-4.46) for all those with low similarity scores (below 0.4), irre-spective of cephalosporin generation. The higher risk associatedwith aminocephalosporins was observed whether penicillin al-lergy was IgE- or T-cellemediated. Eleven observational studieson carbapenem cross-reactivity involving 1127 penicillin-allergicpatients showed that the risk of cross-reactivity to any carba-penem was 0.87% (95% CI, 0.32-2.32). CONCLUSIONS: Although it remains possible that these meta-analyses overestimated the risk of cross-reactivity, cliniciansshould consider the increased risk of cross-reactivity associatedwith aminocephalosporins, and to a lesser extent withintermediate-similarity-score cephalosporins, compared with thevery low risk associated with low-similarity-score cephalosporinsand all carbapenems when using beta-lactams in patients with asuspected or proven penicillin allergy.