Discussion and Summary The present data show a dramatic age-related decrease in cell-mediated immunity as measured by in vitro3H-dThd incorporation by PHA-stimulated mouse spleen cells. Thus, not only is there a marked decline in humoral immune responsiveness during senescence (5), but it now appears that a significant decrease in cell-mediated immunity also occurs. It has been recently reported from this laboratory by Peterson et al. (18), that spleen cells from aged animals are less effective in producing acute mortality in the classical graft-versus-host reaction. Concurrently with these studies, Goodman and Makinodan (19) have observed a marked decrease in cell-mediated immune responsiveness assessed by in vivo allogeneic tumor resistance and in vitro cytolytic activity. Walford and associates (20) have also recently reported a decline in cell-mediated immunity as measured by the in vitro mixed lymphocyte reaction. The present and aforementioned systematic studies were all carried out in inbred mice, where variation between individuals of a given age group is minimized, hence significant quantitative changes can be accurately determined. Although each study assessed cellular immune competence by a different immunologic parameter, all noted a significant decline in cell-mediated immunity. Combined, they provide evidence that cell-mediated immunity declines with age in long-lived inbred mice. It is of course recognized that these findings must be confirmed in other species and cannot necessarily be extrapolated to man; nevertheless, they lend credence to the concept that an age-related decline of cell-mediated immunity may play an exacting role in carcinogenesis and other age-related diseases. It should be noted that the present results confirm the data reported by Rodney et al. (16) showing an age-related decline in the in vitro spleen cell response to PHA in three strains of mice that are generally susceptible to autoimmune disease but stand in sharp contrast to their findings in autoimmune insusceptible CBA mice.