There is a theoretical concern that clinically-significant immunologically-mediated hypersensitivity occurs between beta-lactams sharing side chains, unconfirmed by challenge data. The population-based “allergy” incidence associated with beta-lactam use that share exact R1 sidechains, ampicillin, cephalexin, or cefaclor (ACC), with or without a current ACC “allergy” has not been reported. All courses of ACC, and for comparison trimethoprim-sulfamethoxazole, used by greater than 8 million total Kaiser Permanente California members in 2017 and 2018, with follow-up through January 2019, were identified along with all new antibiotic-specific “allergies” reported within 30 days of course initiation. There were 1,222,045 individuals without and 15,235 with an ACC “allergy” who received AAC or trimethoprim-sulfamethoxazole. There were 64,353 ampicillin, 1,232,384 cephalexin, 1,008 cefaclor, and 479,075 trimethoprim-sulfamethoxazole courses given to individuals without an ACC ”allergy” resulting in 167 (0.26%) ampicillin, 5,500 (0.45%) cephalexin, 8 (0.79%) cefaclor, and 8,763 (1.83%) sulfonamide antibiotic “allergy” reports. There were 1,019 ampicillin, 4,909 cephalexin, 30 cefaclor, and 17,885 trimethoprim-sulfamethoxazole courses given to individuals with a preexisting ACC ”allergy” resulting in 8 (0.79%) ampicillin, 44 (0.90%) cephalexin, 0 cefaclor, and 568 (3.18%) sulfonamide antibiotic “allergy” reports. The incidence of new ampicillin, cephalexin, cefaclor, or sulfonamide antibiotic “allergy” reports is minimally increased in individuals with a preexisting ampicillin, cephalexin, or cefaclor “allergy” over the baseline incidence in the population. This argues against a clinically-significant immunologically mediated cross-reactivity between beta-lactams sharing side chains in individuals with pre-existing, but unconfirmed, beta-lactam “allergy”. Any previously reported antibiotic “allergy” appears to be a risk factor for reporting a new “allergy”.