Rationale: There is a theoretical concern, unconfirmed by population-based challenge data, that clinically-significant immunologically-mediated hypersensitivity occurs between beta-lactams sharing side chains. The population-based “allergy” incidence associated with the use of beta-lactams sharing exact R1 side chains, [ampicillin, cephalexin, and cefaclor (ACC)], with or without a current ACC or sulfonamide antibiotic “allergy” has not been reported. Methods: All courses of ACC and trimethoprim-sulfamethoxazole, used by any Kaiser Permanente California members in 2017 and 2018, with follow-up through January 2019, were identified along with their preexisting antibiotic “allergy” status and all new antibiotic-specific “allergies” reported within 30 days of course initiation. Results: There were 1,167,713 courses of ACC administered to individuals with no sulfonamide antibiotic or ACC “allergy” and 4,771 (0.41%) new ACC “allergies” were reported. There were 130,032 courses of ACC administered to individuals with a sulfonamide antibiotic “allergy” and no ACC “allergy” and 904 (0.70%) new ACC “allergies” were reported. There were 5,958 courses of ACC administered to individuals with an ACC “allergy”, 2,341 who also had sulfonamide antibiotic “allergy”, and 52 (0.87%) new ACC “allergies” were reported. Conclusions: The incidence of new ampicillin, cephalexin, or cefaclor “allergy” reports is minimally and non-specifically increased when a preexisting ACC or sulfonamide antibiotic “allergy” exists over the baseline incidence in the population. This argues against clinically-significant immunologically-mediated cross-reactivity between beta-lactams sharing exact side chains in individuals with pre-existing, but unconfirmed, beta-lactam “allergy”. Any previously reported, even unrelated, antibiotic “allergy” appears to be a risk factor for reporting a new antibiotic “allergy”.