In many port wine stain (PWS) patients, successful clearing is not achieved even after multiple laser treatments because of inadequate heat generation within the targeted blood vessels. Use of higher radiant exposures has been suggested to improve lesion clearing, but risk of epidermal injury due to nonspecific absorption by melanin increases. It has been demonstrated that cryogen spray cooling (CSC) can protect the epidermis from nonspecific thermal injury during laser treatment of PWS. Inasmuch as epidermal melanin concentration and blood vessel depth vary among patients, evaluation of internal skin temperatures in response to CSC is essential for further development and optimization of treatment parameters on an individual patient basis. We present internal temperature measurements in an epoxy resin phantom in response to CSC and use the results in conjunction with a mathematical model to predict the temperature distribution within human skin for various cooling parameters. Measurements on the epoxy resin phantom show that cryogen film temperature is well below the cryogen boiling point, but a poor thermal contact exists at the cryogen-phantom interface. Based on phantom measurements and model predictions, internal skin temperature reduction remains confined to the upper 400 μm for spurt durations as long as 200 ms. At the end of a 100 ms spurt, our results show a 31°C temperature reduction at the surface, 12°C at a depth of 100 μm, and 4°C at a depth of 200 μm in human skin. Analysis of estimated temperature distributions in response to CSC and temperature profiles obtained by pulsed photothermal radiometry indicates that a significant protective effect is achieved at the surface of laser irradiated PWS skin. Protection of the epidermal basal layer, however, poses a greater challenge when high radiant exposures are used.