A simple, rapid and sensitive method based on an ultra-performance liquid chromatography–tandem mass spectrometry(UPLC–MS/MS)has been developed and validated for the determination of pimavanserin in rat plasma.The analyte was extracted by protein precipitation with methanol and separated on an ACQUITY BEH C18column(100 mm×2.1 mm,1.7μm;Waters,USA),with an isocratic elution of acetonitrile-water containing 10 mM ammonium acetate (70:30, v/v), at a flow rate of 0.2 mL/min for 2.5 min. The analyte and clarithromycin (the intal standard) were detected and quantified in positive ion mode using multiple reaction monitoring transitions at m/z 428.2 → 223.0 for pimavanserin and m/z 748.5 → 589.5 for clarithromycin. Relative coefficient (r) for the calibration curve was more than 0.9980. The intra-day and inter-day precisions(relative standard deviation,RSD%)were less than 13.3% and 10.5%,respectively,and the accuracy(relative error,RE%)was within ± 11.5%.The analytical method was successfully applied to a routine pharmacokinetic study of pimavanserin in rats after oral administration at the dose of 10 mg/kg.