Haloperidol (HPD) is a dopamine receptor blocker and a major causative agent of neuroleptic malignant syndrome. To investigate the influence of HPD on immune responsiveness, the natural killer (NK) cell activity of mice was examined after intraperitoneal administration of HPD for 5 days. NK cell activity was markedly decreased without a depletion of NK cells. Bromocriptine (BROMO), which is used for the treatment of neuroleptic malignant syndrome, also decreased NK cell activity. The suppressive effect on NK cell activity was inhibited by injecting both HPD and BROMO simultaneously. Serum levels of prolactin (PRL) decreased after BROMO injection, although serum PRL level was not decreased after the combined administration of HPD and BROMO agents. The reduction of NK cell activity caused by BROMO and by HPD was prevented by the co-injection of PRL and by a beta-adrenergic blocker, respectively. These results indicate that HPD decreases NK cell activity in a PRL-independent manner and that BROMO decreases it via PRL reduction. It seems that the PRL-independent suppressive effect of HPD on NK cells, which is neutralized by BROMO, is mediated by splenic sympathetic function via the beta-adrenergic receptor system. Therefore, BROMO helps to alleviate the depressed NK cell activity caused by HPD therapy.