Purpose: To establish an appropriate quality control method for Xiaojin pills using high-performance liquid chromatograph-tandem mass spectrometry combined with multivariate analysis. Methods: High-performance liquid chromatograph-tandem mass spectrometry was established to detect and quantify 13 chemical components of Xiaojin Pills. In order to evaluate the quality difference between diverse specimens of Xiaojin Pills, several multivariate statistical techniques were applied to analyze the dissimilarity between different batches of samples, including principal composition analysis method and clustering methodology. Results: Five chemical components were identified as primary quality markers, which can be used to accurately distinguish various samples and command the quality of Xiaojin Pills. Conclusion: The results afford a professionally scientific basis for the quality monitoring of Xiaojin Pills and also furnishes reasonable ideas and suggestions for the quality control of other traditional drugs.