Three hydrophobic drugs were analyzed with excellent peak shape on the core-shell mixed-mode column. Poor peak shape is very often observed when hydrophobic basic drugs, like dextromethorphan and trimipramine, are analyzed by traditional reversed-phase chromatography. This poor peak shape is caused by the interaction with residual silanol groups on the surface of RP columns. Since the amounts of these groups are not great, easy overloading and tailing occur. In case of mixed-mode chromatography, the polar basic group on the surface of silica gel provides a shielding effect, preventing the interaction of basic groups of analyte and acidic residual silanols. The mixed-mode core-shell column also has a high capacity towards retention of acidic drugs, which contributes to the good peak shape and retention. Method and column can be used to develop robust and reproducible methods for a hydrophobic basic, hydrophilic acidic and hydrophobic acidic compounds and counter-ions.