Necrosis, as opposed to apoptosis, is recognized as a nonspecific cell death that induces tissue inflammation and is preceded by cell edema. In non-neuronal cells, the latter has been explained by defective outward pumping of Na+ caused by metabolic depletion or by increased Na+ influx via membrane transporters. Here we describe a novel mechanism of swelling and necrosis; namely the influx of Na+ through oxidative stress-activated nonselective cation channels. Exposure of liver epithelial Clone 9 cells to the free-radical donors calphostin C or menadione induced the rapid activation of an approximately 16-pS nonselective cation channel (NSCC). Blockage of this conductance with flufenamic acid protected the cells against swelling, calcium overload, and necrosis. Protection was also achieved by Gd3+, an inhibitor of stretch-activated cation channels, or by isosmotic replacement of extracellular Na+ with N-methyl-D-glucamine. It is proposed that NSCCs, which are ubiquitous although largely inactive in healthy cells, become activated under severe oxidative stress. The ensuing influx of Na+ initiates a positive feedback of metabolic and electrolytic disturbances leading cells to their necrotic demise.