The study examined the effect of repeated amitriptyline administration to mice on the proliferative activity of lymphocytes in response to mitogen stimulation and on the ability of natural killer (NK) cells to evoke lysis of YAC-1 tumor cells in vitro. A relatively short treatment (5 days) produced an increase in the NK activity, but no change in the T cell proliferative response to mitogens. After a 2-week treatment, a transient but significant decrease in the proliferative activity of splenocytes and in the NK activity was observed. Prolonged administration of that drug for more than 3 weeks produced a return to the control level of the NK activity and the T lymphocyte responsiveness to mitogens. The obtained results show that amitriptyline modifies the immune function, and that the observed effect depends crucially on the length of drug administration.