T-cell large granular lymphocytic leukemia (T-LGL) is a rare hematologic neoplasm characterized by clonal expansion of CD3+ cytotoxic T lymphocytes and a highly heterogeneous clinical course. Conventional therapy primarily includes immunosuppressive regimen. However, optimal front-line approaches still need to be defined and refractory disease remains a clinical challenge. Thus, we here aimed to explore functional dependencies of T-LGL as a basis for personalized therapeutic strategies. We performed functional apoptosis profiling and ex vivo drug treatment in a series of 6 clinically and genetically characterized T-LGL patients from two German University hospitals. Our series of 6 patients underscored the clinical and genetic heterogeneity of the disease. Genetically, only 2 patients harbored a STAT3 mutation. To identify targetable anti-apoptotic mechanisms, we performed selective functional BH3 profiling on the patients’ T-LGL versus the same patients’ normal T-cells. T-LGL cells in 50% of the patients (3/6) demonstrated a dominant functional dependence on MCL-1 as compared to the same patients’ normal T-cells. Accordingly, T-LGL cells from patients with enhanced MCL1 dependence significantly responded to AZD-5991 ex vivo while no response was observed in the remaining samples lacking enhanced MCL-1 dependence. Across clinically and genetically heterogeneous cases of T-LGL, functional apoptosis profiling identified patients with dominant dependence on MCL-1 and provided a basis for a targeted therapeutic approach.