We found that tumor necrosis factor alpha (TNFalpha)-induced apoptosis in HeLa cells was accompanied by a approximately 2-fold increase in H- and L-ferritin and a decrease in transferrin receptor, two indices of increased iron availability. Iron supplementation and overexpression of H-ferritin or its mutant with an inactivated ferroxidase center reduced by about approximately 50% the number of apoptotic cells after TNFalpha-treatment, while overexpression of L-ferritin was ineffective. The data indicate that H-ferritin has an anti-apoptotic activity unrelated to its ferroxidase activity and to its capacity to modify cellular iron metabolism.