We demonstrate a novel nonintrusive technique based on tunable diode laser absorption spectroscopy to investigate human sinuses in vivo. The technique relies on the fact that free gases have spectral imprints that are about 10.000 times sharper than spectral structures of the surrounding tissue. Two gases are detected; molecular oxygen at and water vapor at . Light is launched fiber optically into the tissue in close proximity to the particular maxillary sinus under study. When investigating the frontal sinuses, the fiber is positioned onto the caudal part of the frontal bone. Multiply scattered light in both cases is detected externally by a handheld probe. Molecular oxygen is detected in the maxillary sinuses on 11 volunteers, of which one had constantly recurring sinus problems. Significant oxygen absorption imprint differences can be observed between different volunteers and also left-right asymmetries. Water vapor can also be detected, and by normalizing the oxygen signal on the water vapor signal, the sinus oxygen concentration can be assessed. Gas exchange between the sinuses and the nasal cavity is also successfully demonstrated by flushing nitrogen through the nostril. Advantages over current ventilation assessment methods using ionizing radiation are pointed out.