Liquid chromatography-tandem mass spectrometry (LC-MS/MS) is a universal method for the quantitative analysis of small molecular drugs in therapeutic drug monitoring (TDM). Alternatively, liquid chromatography-miniature mass spectrometry (LC-Mini MS) is a simple operating technique for quantitative analysis. However, the wide chromatographic peaks and long retention times of TDM samples using the LC-Mini MS system deteriorated the accuracy and efficiency of quantitative analysis. Here, an optimized electrospray ionization (ESI) interface setup with a splitter valve and a capillary needle (I.D. 30 μm and O.D. 150 μm) of the LC-Mini MS system was acquired. The chromatographic peaks were narrower and smoother and the retention time was shorter for TDM compounds. Furthermore, a quantitative analysis method for risperidone and the active metabolite 9-hydroxyrisperidone in plasma was developed based on this optimal LC-Mini MS setup. The results showed that the calibration curves of risperidone and 9-hydroxyrisperidone had good linear ranges of 2-100 ng mL-1 (R2 = 0.9931) and 2-100 ng mL-1 (R2 = 0.9915), respectively. Finally, the matrix effects, recoveries and stability of risperidone and 9-hydroxyrisperidone samples were analyzed. The results satisfied the requirements of quantitative validation in routine TDM procedures.