Blinatumomab, a single-chain, bispecific, T-cell–engaging antibody targeting CD19, is effective in B-precursor acute lymphoblastic leukemia (BCP-ALL), even in the context of chemotherapy-related partial T-cell immunodeficiency. We report 2 patients with BCP-ALL and congenital T-cell immunodeficiency, who obtained an excellent response to blinatumomab. The first, a 6-year-old girl with Schimke immuno-osseous dysplasia (SIOD) and combined immunodeficiency disorder (CID) obtained a minimum residual disease–negative (MRD−) remission of high hyperdiploid BCP-ALL with blinatumomab. At last follow-up, the remission had been sustained for 14 months from diagnosis. The second was a 9-year-old boy with Omenn syndrome and CID who received a mismatched bone marrow transplant from his mother at the age of 4 months and was diagnosed with t(3;11)+ (KMT2A-LARS2) BCP-ALL 9 years after his transplant. He received a 4-drug induction followed by blinatumomab for persistent MRD as a chemotherapy-sparing bridge to transplant and achieved an MRD− remission. T-lymphopenia, whether congenital or acquired, does not compromise the efficacy of blinatumomab.