An optical sensor for highly sensitive detection of carbon monoxide (CO) in sulfur hexafluoride (SF6) 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 SF6. A theoretical analysis and an experimental investigation of the influence of SF6 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.