Abstract: Fluvoxamine is one of the widely used antidepressants in clinical practice, with a narrow treatment window and large individual differences, routine drug concentration monitoring is required. At present, there is no published reference method or reference material for fluvoxamine at home and abroad. This study aims to establish a candidate reference measurement procedure (cRMP) for serum fluvoxamine based on LC-MS/MS for promoting the standardization of its clinical detection. Serum samples were pre-treated by protein precipitation without derivatization. The bracketing calibration method was used for quantitative analysis.The intra-assay precision of the cRMP was: 0.91%～2.35% (n = 10), the inter-assay precision was: 0.23%～1.09% (n = 5), and the total precision was 0.67%～1.30% (n = 25). Recoveries ranged from 97.05% to 102.96%. The limit of detection (LoD) was 0.05 ng/mL, the lowest limit of quantifcation (LLoQ) was 0.50 ng / mL, the linearity was 3.91 to 500.0 ng/mL, the serum matrix did not interfere with this method, and the carry-over of medium and high concentrations to low concentration samples were 0.46% and 0.23%. The cRMP for serum fluvoxamine established in this study has high accuracy and good stability, which provides the basis for promoting the standardization of clinical serum fluvoxamine detection.