Ryanodine receptors (RyRs) are ion channels responsible for the fast release of Ca from the sarco/endoplasmic reticulum to the cytosol and show a selectivity of Ca over monovalent cations. By utilizing a recently developed multisite Ca model in molecular dynamic simulations, we show that multiple cations accumulate in the upper selectivity filter of RyRs, and the small size and high valence of Ca make it preferable to K in competition for space in this confined region of negative electrostatic potential. The presence of Ca in the upper selectivity filter significantly increases the energy barrier of K permeation, while the presence of K has little impact on the Ca permeation. Our results provide the atomistic details of the charge/space competition mechanism for the ion selectivity of RyRs, which ensures the robustness of their Ca release function. The mechanism could be utilized in protein- and nanoengineering for valence selectivity of ion species.