The high selectivities of liquid chromatography and mass spectrometry make liquid chromatography-mass spectrometry one of the most popular tools for quantitative analysis in complex chemical, biological, and environmental systems, while the potential mathematical selectivity of liquid chromatography-mass spectrometry is rarely investigated. This work discussed the mathematical selectivity of liquid chromatography-mass spectrometry by three-way calibration based on the trilinear model, with an application to quantitative analysis of coeluting aromatic amino acids in human plasma. By the trilinear decomposition of the constructed liquid chromatography-mass spectrometry-sample trilinear model and individual regression of the decomposed relative intensity versus concentration, the proposed three-way calibration method successfully achieved quantitative analysis of coeluting aromatic amino acids in human plasma, even in the presence of uncalibrated interferent(s) and a varying background. This analytical method can ease the requirements for sample preparation and complete chromatographic separation of components, reduce the use of organic solvents, decrease the time of chromatographic separation, and increase the peak capacity of liquid chromatography-mass spectrometry. As a "green analytical method", the liquid chromatography-mass spectrometry three-way calibration method can provide a promising tool for direct and fast quantitative analysis in complex systems containing uncalibrated spectral interferents, especially for the situation where the coelution problem is difficult to overcome.