The use of ionic liquid mixtures (IL-IL mixtures) is being investigated for fine solvent properties tuning of the IL-based systems. The scarce available studies, however, evidence a wide variety of mixing behaviors (from almost ideal to strongly nonideal), depending on both the structure of the IL components and the property considered. In fact, the adequate selection of the cations and anions involved in IL-IL mixtures may ensure the absence or presence of two immiscible liquid phases. In this work, a systematic computational study of the mixing behavior of IL-IL systems is developed by means of COSMO-RS methodology. Liquid-liquid equilibrium (LLE) and excess enthalpy (H(E)) data of more than 200 binary IL-IL mixtures (including imidazolium-, pyridinium-, pyrrolidinium-, ammonium-, and phosphonium-based ILs) are calculated at different temperatures, comparing to literature data when available. The role of the interactions between unlike cations and anions on the mutual miscibility/immiscibility of IL-IL mixtures was analyzed. On the basis of proposed guidelines, a new class of immiscible IL-IL mixtures was reported, which only is formed by imidazolium-based compounds.