Cryogen spray cooling (CSC) reduces epidermal damage during laser treatment of various dermatoses. The goal of this study was to determine the heat removal mechanism in skin and quantify the amount in response to CSC. Thermocouples were imbedded in four model substrates with a range of thermal diffusivities, greater than three orders of magnitude in difference, to measure the temperature profiles in response to CSC and sapphire contact cooling, which removes heat completely by conduction. An algorithm solving an inverse heat conduction problem was subsequently used to quantify the amount of heat removal from the substrates using the measured temperatures. The interface thermal conductance and internal temperatures within the substrates were computed by a finite difference algorithm that solved the heat conduction equation. Results verify a marked increase in heat removal and interface thermal conductance with increasing thermal diffusivity. By estimation from the model substrate results, heat removal and interface thermal conductance values for skin were obtained. Data demonstrate that during CSC, evaporation is the dominant heat transfer mechanism in materials with higher thermal diffusivities; however, conductive cooling dominates in substrates with lower thermal diffusivities such as skin.