The effects of chlorpromazine, haloperidol, clozapine and clotiapine on the mitogenic activation of spleen and bone-marrow cells were investigated. The use of two types of treatments (in vitro with 1.5 to 3 x 10(-3) mM for three days and in vivo with 0.3 mM for four days) permitted the demonstration that chlorpromazine was the most effective drug to inhibit DNA synthesis in mitogen stimulated mouse spleen cell cultures. However, in more prolonged in vivo treatments with a lower dose (0.075 mM for two weeks), clozapine and clotiapine frequently appeared as the most active inhibitors of mitogen-induced lymphoblastic transformation. In any case splenic T lymphocytes were more affected than B cells of the same origin. (3H) TdR uptake in DXS-stimulated bone-marrow cell cultures was also variably inhibited by in vivo drug treatments of mice as compared to groups of untreated animals. Occasionally, the effect of the drugs in vivo depend on the length of the treatment, rather than the dose administered. All these inhibitory effects did not appear as a phenomenon of cytotoxicity since doses used in vitro inhibit by less than 5% the cell viability. It is suggested that the variable depressions of the different mitogenic responses, produced by these neuroleptic drugs, may reflect an alteration in the cyclic AMP levels as a consequence of its inhibition of a phosphodiesterase activator.