Early T-cell precursor acute lymphoblastic leukemia (ETP-ALL) is a high-risk T-ALL subtype with distinct immunophenotypes and genetic alterations, complicating diagnosis and treatment. Although cytogenetic and gene expression studies have advanced the diagnostic and therapeutic strategies, the proteomics signatures of ETP-ALL remain underexplored. Herein, we performed 4D label-free proteomic analyses on mononuclear cells isolated from ETP-ALL, T-ALL, acute myeloid leukemia (AML), and healthy donor samples to identify molecular signatures specific to ETP-ALL.