Increasing treatment intensity for pediatric Ewing sarcoma (ES) has improved survival, but comes with an increased incidence of secondary malignancy. Here, we describe a case of therapy-related mixed phenotype acute leukemia (t-MPAL), T-myeloid type, in a pediatric patient four years after completion of therapy for ES. Genomic evaluation revealed a novel and likely pathogenic RUNX1-TAF3 fusion. This patient did not respond to T-cell leukemia-directed therapy, and while he initially responded to myeloid leukemia-directed therapy, he never achieved complete remission and died of disease 10 months after diagnosis. Here, we present this case and review prior literature regarding t-MPAL.