Based upon their in vitro receptor binding profiles, the atypical antipsychotics clozapine and olanzapine exhibit cholinergic receptor binding of similar potency. Data comparing the in vivo anticholinergic effects, however, of these neuroleptics upon neurocardiac control are sparse. The goal of this study was to compare the in vivo effects of clozapine and olanzapine upon neurocardiac control by assessment of the pulse rate variability (PRV) in schizophrenic patients and healthy controls. Twenty patients with schizophrenia (according to DSM-III-R criteria) treated with either clozapine (100-600 mg/day) or olanzapine (10-20 mg/day), and ten healthy controls, were recruited into the study. PRV was assessed by continuously recording the skin blood volume in the fingertip of the second digit under resting conditions and PRV parameters were calculated. When significant differences in PRV parameters between the patients and controls were detected by Kruskal-Wallis tests, Mann-Whitney tests were used to test for group differences between the olanzapine- and clozapine-treated patients. In comparison to the healthy controls, the PRV parameters of the clozapine- and olanzapine-treated schizophrenic patients were significantly reduced. Indeed the reduction of PRV was significantly greater in the clozapine-treated group compared to the olanzapine-treated group (P<0.05). Compared to the controls, only the clozapine-treated patients showed a significantly diminished low-frequency (LF)/high frequency (HF)-ratio, a PRV parameter reflecting sympatho-vagal balance. The significantly greater reductions in PRV parameters of the clozapine-treated compared to olanzapine-treated patients may be caused by clozapine's higher affinity for alpha(1)-adrenergic receptors in vivo compared with olanzapine. The similar LF/HF ratios of the healthy controls and olanzapine-treated patients suggests that the sympathetic-parasympathetic modulation of PRV remains relatively unchanged even during olanzapine treatment.