For a study, it was determined that non-immunoglobulin E (IgE)-mediated hypersensitivity reactions (HSRs) to nafcillin were often reported. However, less data was available to guide significant antibiotic change following these reactions. The purpose of the studies was to describe the tolerability of cefazolin in patients who developed suspected non-IgE-mediated HSR to nafcillin. A study followed a descriptive case series of patients who received nafcillin for an MSSA infection, experienced a non-IgE-mediated HSR, and was switched to cefazolin between October 2015 and November 2019 at a single academic medical center. The primary objective was to examine the percentage of patients who completed cefazolin after experiencing a suspected non-IgE-mediated HSR to nafcillin. It was found that 80 patients with 87 prespecified non-IgE-mediated HSRs during the study period. About 71 (89%) patients completed cefazolin, with 53 (75%) of these patients completing at least 2 weeks of therapy. However, one patient was found to ultimately switch from cefazolin to daptomycin due to concern for treatment failure. Around eight patients (10%) did not tolerate cefazolin after switching from nafcillin. Of these, three patients experienced HSR, whereas five patients experienced the same non-IgE-mediated HSR that was attributed to nafcillin and discontinued cefazolin within seven days. Treatment with cefazolin after experiencing a suspected non-IgE-mediated HSR to nafcillin appeared to be safe according to the studies, even for patients requiring long duration of cefazolin.