We studied the effect of optical clearing (OC) by glycerol, Omnipaque TM (iohexol), and polyethylene glycol on human skin in vivo using a portable Raman spectroscopy system. Kinetic curves were determined for different concentrations of these optical clearing agents (OCAs). The three agents enhanced OC, showing non-monotonic behavior for serial concentrations. The dehydration mechanism also caused a decay in OC during the initial 10−20 min. Furthermore, characteristic Raman signals could be used to identify different areas of skin and tissues. Variations in different skin sites predominantly affected the Raman bands at 462, 683, 883, 1253, 1415, 1450, and 1655 cm −1 .