A rapid gas chromatography-mass spectrometry (GC-MS) method was developed and validated for the analysis of eperisone in serum using monolithic spin-column extraction. The linear concentration range for eperisone was 2-2500 ng/ml. The limit of detection was found to be 0.5 ng/ml. The average extraction recovery range was 92.8-96.0%. The intra- and interday relative standard deviations (RSDs) of the concentrations were less than 12.6% and 12.5%, respectively. The accuracy of this method ranged from 95.0% to 98.3%. We successfully used this assay to analyze serum samples from an eperisone-overdose patient. Our method has some analytical advantages compared with previously reported gas chromatography (GC) and GC-MS methods, such as higher selectivity and sensitivity than GC with nitrogen-phosphorus detection and the avoidance of nonspecificity, the ability to use a smaller sample volume than that required for the GC-MS method, and a shorter sample preparation time than the previous solid-phase extraction (SPE) method.