Optical tissue clearing by hyperosmotic chemical agents significantly increases light depth penetration in skin and may improve light-based therapeutics such as laser treatment of cutaneous vascular lesions. A feasibility study was conducted to evaluate the potential role of optical clearing by glycerol in laser treatment of cutaneous vessels. Optical imaging was performed to investigate the morphological effects of glycerol on blood vessels of skin. Blood vessels were imaged using Doppler optical coherence tomography in in vivo hamster skin treated with glycerol. Images were obtained from the subdermal side to assess morphological changes in the blood vessels caused by glycerol and from the epidermal side to assess enhanced Doppler imaging of blood vessels. Application of glycerol to the subdermis resulted in venule stasis and for prolonged treatment times, arteriole stasis. In cases where flow remained in arterioles, an improved Doppler signal was detected from blood vessels when imaging transepidermally compared with the native condition. Intensity images indicated changes in blood optical properties and improved contrast of skin cross sections after glycerol application. The observed optical and morphological effects were reversed upon hydration of the skin with phosphate-buffered saline. The combination of increased depth of light penetration and the temporary slowing or cessation of flow in blood vessels could mean improved laser treatment of vessels.