The noninvasive determination of glucose in the interstitial layer of the human skin by mid-infrared spectroscopy is reported. The sensitivity for this measurement was obtained by combining the high pulse energy from an external cavity quantum cascade laser (EC-QCL) tunable in the infrared glucose fingerprint region (1000-1220 cm(-1)) focused on the skin, with a detection of the absorbance process by photoacoustic spectroscopy in the ultrasound region performed by a gas cell coupled to the skin. This combination facilitates a quantitative measurement for concentrations of skin glucose in the range from <50 mg/dL to >300 mg/dL, which is the relevant range for the glucose monitoring in diabetes patients. Since the interstitial fluid glucose level is representative of the blood glucose level and follows it without significant delay (<10 min), this method could be applied to establish a noninvasive, painless glucose measurement procedure that is urgently awaited by diabetes patients. We report here the design of the photoacoustic experiments, the spectroscopy of glucose in vivo, and the calibration method for the quantitative determination of glucose in skin. Finally, a preliminary test with healthy volunteers and volunteers suffering from diabetes mellitus demonstrates the viability of a noninvasive glucose monitoring for patients based on the combination of infrared QCL and photoacoustic detection.