Agmatine, an endogenous metabolite of arginine, selectively suppresses growth in cells with high proliferative kinetics, such as transformed cells, through depletion of intracellular polyamine levels. Studies have reported increased oxidative stress and induction of apoptosis in settings of polyamine depletion utilizing the ODC inhibitor difluoromethyl ornithine (DFMO). Here we deplete intracellular polyamine content with agmatine to determine if attrition by cell death contributes to the growth suppressive effects. We do not observe an increase in necrosis, DNA fragmentation or chromatin condensation in H-ras transformed NIH-3T3 cells (Ras/3T3) administered agmatine. In response to calcium induced oxidative stress in kidney mitochondrial preparations, agmatine demonstrates attributes of a free radical scavenger by protecting against oxidation of sulfhydryl groups and decreasing hydrogen peroxide content. The functional outcome is a protective effect against calcium induced mitochondrial swelling and mitochondrial membrane potential collapse. We also observe decreased expression of pro-apoptotic BCL-2 family members and of execution caspase-3, implying anti-apoptotic potential. Indeed, we find apoptosis induced by camptothecin or 5-fluorourocil attenuated in cells administered agmatine. Agmatine may offer an alternative to DFMO for depleting intracellular polyamine content while avoiding the complications of increasing polyamine import and reducing the intracellular free radical scavenger capacity of polyamines. Depletion of intracellular polyamine content with agmatine suppresses cell growth, yet its antioxidant capacity affords protection from mitochondrial insult and resistance to cellular apoptosis. These results could explain the beneficial outcomes observed with agmatine in models of injury and disease.