We previously reported that mitogen-induced proliferative responses of lymphocytes in the elderly were significantly lower than in young individuals. To determine when this decline occurs, we evaluated the responses of 26-30 subjects of each decile from the third to the tenth decile to the T cell mitogens, phytohaemagglutinin (PHA) and concanavalin A (ConA), and the T dependent B cell mitogen, pokeweed mitogen (PWM). There was a significant decrease in the responses of the 70-, 80- and 90-year-olds to PHA and ConA (less than 40% of the 20-year-olds; P less than 0.01). The 80- and 90-year-olds also showed a decreased response to PWM (approximately 50%; P less than 0.01). The 60-year-olds showed a decreased response to all three mitogens but only the PHA and ConA responses were significantly decreased (P less than 0.01). The 50-year-olds showed a decreased response to ConA, while the 40-year-olds showed decreased responses to both PHA and ConA; both significant at P less than 0.01. The decreased response of the 40-year-olds, however, was only seen in the females. This may be due to the hormonal changes associated with menopause. The general trend of the data suggests that there is a gradual decrease in mitogen-induced proliferative responses with increasing age, large differences become apparent at the age of 60, with a further decrease in the 70s, and most importantly, they remain fairly constant thereafter. Of interest is that only three of the 111 subjects less than 60 years old failed to mount a proliferative response and in each case this was to only one mitogen, while 42 of 118 subjects greater than 60 years old did not respond to at least one mitogen. Ten of these older subjects (2/28 of the 60-year-olds) did not respond to any of the three mitogens (P less than 0.01). This lack of response may be important since we have found a significant association between the lack of response to all three mitogens and increased mortality.