BACKGROUND: Modifying additives to alter the selectivity of a single stationary phase and solvent system is appealing in mixed-mode separations. Silica-bonded cyclofructan-6 uniquely binds with cations strongly in the presence of organic solvents and is hydrolytically stable. Perchlorate with inorganic and organic quaternary ammonium cations could adjust retention for molecules with carboxylic acids, sulfonic acids, and nitrogen-containing functional groups, which are common in pharmaceutically relevant molecules. Perchlorate salts of ammonium, lithium, tetrabutylammonium, and tetramethylammonium were assessed for their selectivity in acetonitrile-water eluent systems. RESULTS: This study provides a mathematical route to accomplish complex selectivity alterations by simply varying the perchlorate counterions. Two predictive tests based on l SIGNIFICANCE: The proposed mathematical tests will assist chromatographers in selecting distinct eluent additives for different classes of separations during method development. The applicability of the eluent selection strategy has been shown with the separation of three different biologically important classes of molecules containing analytes like cocaine, amphetamine, tianeptine, serotonin, lorazepam, and 5-fluorouracil.