TRAP1 is a mitochondrial chaperone highly expressed in many tumor types; it inhibits respiratory complex II, down-modulating its succinate dehydrogenase (SDH) enzymatic activity. SDH inhibition in turn leads to a pseudohypoxic state caused by succinate-dependent HIF1α stabilization and promotes neoplastic growth. Here we report that TRAP1 inhibition of SDH also shields cells from oxidative insults and from the ensuing lethal opening of the mitochondrial permeability transition pore. This anti-oxidant activity of TRAP1 protects tumor cells from death in conditions of nutrient paucity that mimic those encountered in the neoplasm during the process of malignant accrual, and it is required for in vitro tumorigenic growth. Our findings demonstrate that SDH inhibition by TRAP1 is oncogenic not only by inducing pseudohypoxia, but also by protecting tumor cells from oxidative stress.