Abstract: AimTo develop and validate a liquid chromatographic-tandem mass spectrometric (LC-MS/MS) method for the determination of risperidone in human plasma. MethodsRisperidone and the internal standard, diphenhydramine, were isolated from plasma by liquid-liquid extraction with ether-dichloromethane (3∶2, v/v), then chromatographed on a Zorbax Extend-C₁₈ column (150 mm×4.6 mm ID, 5 μm) using a mobile phase consisted of acetonitrile-water-formic acid (40∶60∶0.5, v/v), at a flow rate of 0.7 mL·min^-1. A Finnigan TSQ tandem mass spectrometer equipped with atmospheric pressure chemical ionization source was used as detector and was operated in the positive ion mode. Selected reaction monitoring (SRM) using the precursor product ion combinations of m/z 411→191 and m/z 256→167 were used to quantify risperidone and diphenhydramine (IS), respectively. ResultsThe linear concentration range of the calibration curve for risperidone was 0.025-50 μg·L^-1. The lower limit of quantification was 0.025 μg·L^-1. The intra- and inter-day relative standard deviation (RSD) across three validation running over the entire concentration range was less than 7.1%. The accuracy was within ±3.8%. Each sample was chromatographed within 2.7 min. ConclusionThe method was proved to be rapid, sensitive and suitable for pharmacokinetic investigations of risperidone.