[en] A quantum mechanics (QM) calculation and molecular dynamics (MD) simulation are performed to investigate the interaction of 5-fluorouracil (5-Fu) anticancer drug with covalent organic frameworks (COFs). QM results indicate that the drug adsorption process on COF surface is exothermic, and the optimized complexes are stable. Furthermore, it is found that the hydrogen bond and π–π interactions are the most important factors in the stabilization of the COF/5-Fu complexes. The calculated electron densities and Laplacian at the intermolecular bond critical points using atoms-in-molecule method indicate the intermolecular interactions between COF and drug molecules have ‘electrostatic’ character. The natural bond orbital analysis indicates that the charge has been transferred from COF to 5-Fu in all complexes. MD results confirm that diffusion of 5-Fu molecule into the COF pores is slow and is in the range of the other porous materials, which is a crucial factor for the controlled drug release. (paper)