Most antipsychotic drugs have cardiac effects as a consequence of their pharmacological actions. Recently, thioridazine has been subjected to a restricted indications notice and sertindole had its license withdrawn because of concerns about their potential cardiotoxicity. In the development of new atypical agents, heart-rate corrected QT effects are evaluated but it is unclear how predictive these are of clinically significant cardiotoxicity or sudden death. Heart rate variability (HRV) is a potential index of cardiotoxicity which has been found to be decreased following antidepressants and clozapine. We studied acute HRV changes following antipsychotic agents. Sixteen healthy male volunteers received risperidone (4 mg), olanzapine (10 mg), thioridazine (50 mg) or placebo in a randomized cross-over design. Subjective effects and psychomotor function were assayed at 2 h and both linear (summary statistics) and non-linear (scatterplot) measures of HRV were evaluated by continuous electrocardiogram recording over 10 h. Differential effects of single doses of the three antipsychotic drugs on HRV were found, and these were independent of their sedative effects. Olanzapine increased, and thioridazine decreased HRV, while risperidone had no effect. HRV is sensitive to the acute effects of antipsychotics. It may prove to be a reliable index of their potential for cardiotoxicity. Further studies in both healthy volunteers and patients on antipsychotic medication will be valuable.