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An optical sensor for highly sensitive detection of carbon monoxide (CO) in sulfur hexafluoride (SF 6 ) was demonstrated by using the quartz-enhanced photoacoustic spectroscopy technique. A spectrophone composed of a custom 8 kHz T-shaped quartz tuning fork with grooved prongs and a pair of resonator tubes, to amplify the laser-induced acoustic waves, was designed aiming to maximize the CO photoacoustic response in SF 6 . A theoretical analysis and an experimental investigation of the influence of SF 6 gas matrix on spectrophone resonance properties for CO detection have been provided, and the performances were compared with the standard air matrix. A mid-infrared quantum cascade laser with a central wavelength at 4.61 μm, resonant with the fundamental band of CO, and an optical power of 20 mW was employed as the light excitation source. A minimum detection limit of 10 ppb at 10 s of integration time was achieved, and a sensor response time of ∼3 min was measured.