Core-shell mixed-mode columns offer unique selectivity which comes from the presence of two mechanisms – reversed-phase and ion-exchange. The alternative selectivity of mixed-mode columns can be used when order of elution or resolution between compounds needs improvement. Even for neutral compounds a different selectivity can be obtained. A method for common components of headache medications (acetaminophen, caffeine, and benzoate) was developed on our Coresep 100 column. Efficiency and peak shape are comparable to leading brand core-shell reversed-phase columns.