This dataset contains the LC×LC–DAD–MS raw experimental data supporting the results reported in the associated research article "Chemometrics in comprehensive two-dimensional liquid chromatography: A study of the data structure and its multilinear behavior" (DOI: 10.1016/j.chemolab.2020.104009). The data correspond to the analysis of a complex mixture of 31 pharmaceutical compounds using comprehensive two-dimensional liquid chromatography coupled to diode-array UV detection and triple-quadrupole mass spectrometry with electrospray ionization operated in both positive and negative modes. The dataset includes nine Common Data Format (.CDF) files, corresponding to three analyzed samples: one blank sample and two injections of the pharmaceutical mixture.Each sample is provided as three separate files, corresponding to different detection modes. The numerical suffix in the file name indicates the data function: Suffix “1”: ESI-MS positive mode (MS⁺) Suffix “2”: ESI-MS negative mode (MS⁻) Suffix “3”: UV-DAD data (190–600 nm) AcknowledgementsThe research leading to these results has received funding from the Spanish Ministry of Science and Innovation (MCI, Grant CTQ2017-82598-P). The authors also want to grant support from the Catalan Agency for Management of University and Research Grants (AGAUR, Grant 2017SGR753) and Spanish Ministry of Science and Innovation (MCI, Project CEX2018-000794-S). MPC acknowledges a predoctoral FPU 16/02640 scholarship from Spanish Ministry of Education and Vocational Training (MEFP).