This study presents a rapid, specific and sensitive liquid chromatography/tandem mass spectrometry (LC-MS/MS) assay for determination of risperidone (RIS) in human serum using paroxetine as an internal standard (IS). An Alltima-C18 column (2.1 mmx100 mm, 3 microm) and a mobile phase consisting of 0.1% formic acid-acetonitrile (40:60, v/v) were used for separation. The analysis was performed by selected reaction monitoring (SRM) method, and the peak area of the m/z 411.3-->191.1 transition for RIS was measured versus that of the m/z 330.1-->192.1 transition for IS to generate the standard curves. The assay linearity of RIS was confirmed over the range 0.25 approximately 50.00 ng/ml and the limit of quantitation was 0.05 ng/ml. The linear range corresponds well with the serum concentrations of the analytes obtained in clinical pharmacokinetic studies. Intraday and interday relative standard deviations were 1.85% approximately 9.09% and 1.56% approximately 4.38%, respectively. The recovery of RIS from serum was in the range of 70.20% approximately 84.50%. The method was successfully applied to investigate the bioequivalence between two kinds of tablets (test versus reference products) in 18 healthy male Chinese volunteers. The result suggests that two formulations are bioequivalent.