Cetylpyridinium chloride is hydrophobic basic compound and triethylene glycol is hydrophilic neutral compounds. Quantitative analysis of both compounds is problematic due to a different nature of these two analytes. Both compounds were analyzed on an Obelisc N column in HILIC/cation-exchange mode. Cetylpyridinium chloride is retained by cation-exchange mechanism, and triethylene glycol is retained by HILIC mechanism. Mixed-mode HILIC approach allows to retain compounds either based on multiple or single mechanisms interaction, thus providing a valuable approach for analysis. Cetylpyridinium chloride and triethylene glycol can be monitored by combination of UV and ELSD/CAD.