Cononsolvency is a phenomenon for which the solubility of a macromolecule decreases or even vanishes in the mixture of two good solvents. Although it has been widely applied in the physicochemical, green chemical, and pharmaceutical industries, its origin is still under active debate. Here, by using combined neutron total scattering, deuterium-labeling, and all-atom molecular dynamic simulations, we demonstrated that it is the strong water/cosolvent attraction that leads to the cononsolvency, both competitive hydrogen bonding and water/cosolvent complexation are its results. The combined approach presented here has opened a new route for investigating the most probable all-atom structure in macromolecular solutions.