Introduction/Objective Therapy-related mixed phenotype acute leukemia (Tr-MPAL) is a rare and aggressive disease comprising blast cells of more than one hematopoietic cell lineage. There is limited patient outcome data with this diagnosis. Hence, we present two such cases with clinicopathologic correlation. Methods/Case Report Clinical and pathology data were obtained from institutional electronic health records for two cases of Tr-MPAL identified in the past three years (2018-2020). Results (if a Case Study enter NA) Case 1: 60-years old female, history of chemo-radiotherapy for breast carcinoma, had 49% circulating dimorphic blasts. By immunophenotype, blasts were positive for CD34, CD117, HLA-DR, cCD3, TdT, CD13, CD15, CD38, CD2, CD7, and MPO by cytochemistry, negative for B-cell lineage markers, consistent with Tr-MPAL, T/Myeloid. Ancillary studies revealed normal female karyotype, FLT3-ITD positivity, and DNMT3A frameshift mutation. The patient achieved remission with ALL regimen Hyper-CVAD/methotrexate-cytarabine and underwent an allogeneic stem cell transplant (SCT). The patient was disease-free and on maintenance therapy post 2 years of initial diagnosis. Case 2: 49-years old female, history of chemotherapy for breast carcinoma, had 77% circulating dimorphic blasts (MPO+/PAX5- and MPO-/PAX5+/CD79a+). By immunophenotype, blasts were positive for CD34, CD117, HLA-DR, CD13, CD33, CD15, CD11b, CD19+(dim), cytoCD79a(subset), MPO(subset) and negative for CD14, CD10, CD7, CD8, cCD3, cCD22, and TdT, consistent with Tr-MPAL, B/Myeloid. Ancillary studies revealed normal female karyotype, FLT3-ITD positivity, mutations in RUNX1(frameshift insertion S318fs), SETD2(frameshift insertion P1403fs), WT1(frameshift deletion T377fs), ATM (LI555H), CREBBP (P84S), and DNMT3A (W305). The patient was treated with ALL regimen Hyper-CVAD/methotrexate-cytarabine but relapsed in the post-induction phase with a similar genetics profile. Once remission was achieved, the patient underwent allogeneic SCT and is disease-free while on maintenance therapy post 18 months of initial diagnosis. Conclusion Phenotypically different Tr-MPAL also differ by their underlying genetic abnormalities and may vary in response to therapy. A large cohort of cases may provide us further insights into the genetics and survival outcome of this therapy-related leukemia subtype.