The level of inositol 1,4,5-triphosphate (Insl,4,5P 3) was determined in human and rabbit red blood cells of different ages. In human erythrocytes, fractionated by discontinuous density gradient centrifugation, Ins1,4,5,P 3 was 290 nM in the 0.3% low density (youngest) cells compared to values of 107 nM in the whole red blood cell population. A progressive increase in Ins1,4,5P 3 was then observed during erythrocyte aging from values of 63 nM in mature erythrocytes to 128 nM in the oldest cells. Determinations of Ins1,4,5P 3 in rabbit erythrocytes provided values of 180 nM. Phenylhydrazine was administered to three animals to induce reticulocytosis. Ins1,4,5P 3 in rabbit reticulocytes was significantly lower than in the whole red cell population, remained lower in young red blood cells and then increased to normal values during cell maturation. These results provide evidence for an increase of Ins1,4,5P 3 during red blood cell aging and could contribute to explain the age-dependent loss of deformability and of Ca 2+ homeostasis of these cells.