Peripheral lymphocytes from young persons were found to increase the content of labile triosephosphate isomerase (TPI) following pokeweed mitogen stimulation in vitro. The labile form appears to have the same thermal inactivation pattern as a tetradeamidated form of the enzyme previously shown to accumulate in fibroblasts and lymphoblasts. Human lymphocytes from an elderly sample were also subjected to mitogen stimulation under identical conditions. There was a greater accumulation of labile TPI during lymphoblast transformation in the aged sample. Cellular studies revealed that the absolute level of tritiated thymidine incorporated into DNA was significantly decreased with age in both resting and stimulated lymphocytes, but the blastogenic index showed no significant age-dependent changes. The ratio of the accumulation of labile enzyme during mitogen stimulation to the cellular blastogenic index was increased with age. The accumulation of labile forms of this enzyme may relate to the impairment of the energy-supplying glycolytic pathway that occurs in elderly human lymphocytes subjected to mitogenic stress.