Background: Propylene glycol (PG) and butylene glycol (BG) are not known to be cross-reactors. However, no large-scale studies have assessed the cross-reactivity rate (CRR) between these 2 structurally and functionally similar compounds. Objectives: The aim of this study was to determine whether PG and BG demonstrate cross-reactivity. Methods: This is a retrospective chart review of 893 patients who underwent patch testing for both PG and BG from 2020 to 2022. The frequencies of positive reactions and concomitant reaction rates were calculated. Results: In our cohort, 53 (5.94%) patients reacted to PG and 13 patients (1.46%) reacted to BG. Of the patients who reacted to PG, 6 reacted to BG representing a CRR of 11.3%, whereas the CRR to PG in BG-allergic patients was 46.2%. Conclusions: For those allergic to BG, PG should be considered a cross-reactor. This relationship is somewhat unidirectional, as patients allergic to PG demonstrated a CRR to BG of only 11.3%, significantly lower than the 46.2% CRR to PG among BG-allergic patients.