Majority of the drugs in pharmaceutical industries are administered in a salt form. The presence of two counter-ions very often requires two methods. The nature of these counterparts in drugs can be: inorganic cation and organic acid, inorganic anion and organic base, and organic cation and organic anion. Based on the property of molecules the stoichiometry can be different also. The task of simultaneous quantitation of counter-ions can be achieved by using mixed-mode columns. The general approach for analysis is based on properties of corresponding counter-ions. Hydrophobic basic drugs, like dextromethorphan, verapamil, trimipramine, and corresponding acidic counter-ions (chloride, chlorate, bromide, bromate, perchlorate, maleate, fumarate,tartrate, succinate, phosphate, citrate, benzosulfonate, toleuensulfonate) can be separated and quantitated in the same run on reversed-phase anion-exchange column. Basic hydrophobic drugs are retained by reversed-phase mechanism, and counter-ion are retained by reversed-phase and anion-exchange mechanism. Some polar counter-ions are retained only by anion-exchange mechanism. Retention time and selectivity of HPLC separation of drugs and counter-ions can be achieved by changing amount of acetonitrile and amount of ions in the mobile phase. Detection technique depends on the properties of counter-ions. In case of low or no UV activity, ELSD can be employed if counter-ion forms non-volatile salt wit mobile phase additive (ammonium formate). This HPLC method can be used for simultaneous quantitation of other basic drugs and counter-ions. Presence of two mechanisms of retention allows to control retention times of drug and counter-ion independently, and even change order of elution when necessary.