Proton-transfer-reaction (PTR) mass spectrometry (MS) is capable of detecting trace-level volatile organic compounds (VOCs) in gaseous samples in real time. Therefore, PTR-MS has become a popular method in many different study areas. Most of the currently reported PTR-MS applications are designed to determine volatile compounds. However, the method might be applicable for nonvolatile organic compound detection. Supercritical fluid chromatography (SFC) has been studied in the last 5 decades. This approach has high separation efficiency and predictable retention behavior, making separation optimization easy. Atmospheric ionization techniques, such as atmospheric chemical ionization (APCI) and electrospray ionization (ESI), are the most studied SFC-MS interfaces. These processes require the addition of makeup solvents to prevent precipitation or crystallization of the solute while depressurizing the mobile phase. In contrast, the PTR process is carried out in a vacuum; supercritical carbon dioxide may release solute into the PTR flow tube without a phase transition as long as it is maintained above a critical temperature. Therefore, this might constitute yet another use for the SFC-MS interface. Caffeine and a few other nonpolar compounds in supercritical carbon dioxide were successfully detected with time-of-flight MS without adding solvent by using preliminarily assembled supercritical flow injection and supercritical fluid extraction (SFE)-PTR interfaces.