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Simple Summary: Asparaginase allergy is the most common side effect of childhood acute lymphoblastic leukemia (ALL) therapy and may affect survival outcomes, but the basis of T-cell responses—especially the T-cell receptor (TCR) repertoire—is unknown. The aim of this study was to characterize the associations of TCR repertoire diversity with the risk of allergy. We found that a TCR repertoire that was more varied and changed more during therapy was associated with an increased risk of clinical allergy and decreased asparaginase activity later in therapy. A higher variability of the repertoire between timepoints was predictive of the occurrence of allergy. After an allergy had occurred, the TCR repertoire became altered and more similar. Understanding the immunological basis of this common toxicity in childhood ALL helps in the development of more effective methods to predict or mediate this event. Asparaginase is a critical component of therapy for childhood acute lymphoblastic leukemia (ALL), but it is commonly associated with allergy, which results in morbidity and poorer outcomes. The underlying basis of this allergy is undoubtedly immune-mediated, but the exact components of T-cell immunity have yet to be characterized. We performed longitudinal TCR sequencing of 180 bone marrow samples from 67 children with B-ALL treated as part of the Ma-Spore-ALL-2010 trial, and we evaluated the associations of TCR profile with asparaginase hypersensitivity, with functional validation of asparaginase activity in a separate cohort of 113 children. We found that a more diverse and dynamically changing TCR repertoire was associated with increased risk of clinical hypersensitivity and decreased L-asp activity. Allergic patients had a higher proportion of infrequent clonotypes, as well as a significantly lower degree of shared clonotypes amongst the cohort. Allergic patients also had significantly higher longitudinal variability of clonotypes across timepoints, where a higher dissimilarity between diagnosis and week 5 represented an 8.1-fold increased risk of an allergic event. After an allergy had occurred, there was shaping and convergence of the TCR repertoire towards a common antigen. Understanding the immunological basis of T-cell responses in allergy lays the groundwork for developing predictive biomarkers or strategies to mediate this common toxicity in childhood ALL. [ABSTRACT FROM AUTHOR]