Abstract: OBJECTIVE To investigate the effect of heat-inactivation of blood samples on therapeutic drug monitoring (TDM) of atypical antipsychotics. METHODS Since plasma sample was collected, it was heated at 56℃ for 30 min, and then extracted by protein precipitation. High performance liquid chromatography tandem mass spectrometry was employed for quantification of risperidone, paliperidone(9-OH risperidone), olanzapine, quetiapine, aripiprazole and amisulpride. Matrix effects, accuracies and precisions of quality control samples after inactivation were investigated. Paired sample t-test was used to evaluate the difference of the concentration of the clinical samples before and after inactivation. RESULTS Related standard deviations(RSD) of internal standard normalized matrix factors or low, middle and high concentrations of the 6 compounds after inactivation were all less than 15%. Inter and intra batch accuracies were within ±15% and those of precisions were under 15%. No difference was found before and after inactivation for risperidone, paliperidone, olanzapine, quetiapine and aripiprazole, while which of amisulpride was significant different(P<0.05). CONCLUSION Heat-inactivation at 56℃ for 30 min can be applied in TDM samples containing risperidone, paliperidone, olanzapine, quetiapine and aripiprazole, while the concentration of amisulpride is significantly increased and therefore heat-inactivation is not appropriate for samples containing amisulpride.