A method to quantify eight carbonyl compounds in mainstream cigarette smoke is presented using ultra-high pressure liquid chromatography (UHPLC). The combination of UHPLC and mass spectrometry (UHPLC-MS) dramatically reduces analysis times as compared to the current in-house high-performance liquid chromatography (HPLC)-UV method. In addition, improved detector selectivity and peak resolution are observed. Sample analysis times are reduced from 47 min with HPLC-UV to less than 5 min using this improved method. Atmospheric pressure chemical ionization, atmospheric pressure photo ionization, and electrospray ionization are directly compared to evaluate ionization potential and linear response range for the carbonyl 2,4-dinitrophenylhydrazine derivatives. Smoke extracts from three standard smoking protocols are analyzed by both UHPLC-MS and HPLC-UV for method comparison purposes.