Prohibitins (PHB1 and PHB2) have been proposed to play important roles in cancer development and progression, however their oncogenic mechanism of action has not been fully elucidated. Previously, we showed that the PHB1 and PHB2 protein complex is required for mitochondrial homeostasis and survival of normal human lymphocytes. In this study, novel evidence is provided that indicates mitochondrial prohibitins are overexpressed in hematologic tumor cells and promote cell survival under conditions of oxidative stress. Immunofluorescent confocal microscopy revealed both proteins to be primarily confined to mitochondria in primary patient lymphoid and myeloid tumor cells and tumor cell lines, including Kit225 cells. Subsequently, siRNA-mediated knockdown of PHB1 and PHB2 in Kit225 cells significantly enhanced sensitivity to H 2 O 2-induced cell death, suggesting a protective or anti-apoptotic function in hematologic malignancies. Indeed, PHB1 and PHB2 protein levels were significantly higher in tumor cells isolated from leukemia and lymphoma patients compared to PBMCs from healthy donors. These findings suggest that PHB1 and PHB2 are upregulated during tumorigenesis to maintain mitochondrial integrity and therefore may serve as novel biomarkers and molecular targets for therapeutic intervention in certain types of hematologic malignancies.