This study presents an experimental investigation of the heat transfer performance of a two-phase loop thermosyphon with an enhanced mixed-wettability evaporator surface at sub-atmospheric pressures. For central-processing-unit (CPU) cooling applications, a lowering of the saturation temperature (pressure) is essential when water is used as the working fluid. Compared with copper mirror surfaces, up to over 100% enhancement of high heat transfer coefficient (HTC) was observed using surfaces with spotted wettability patterns, which consists of hydrophobic spots with contact angle ranged from 145° to 150°. The results revealed that the boiling behaviors changed drastically with the application of hydrophobic spots coating by artificially increasing the nucleation site density. Parametric tests with a variety of operating conditions, including different filling ratios, condenser temperatures, and heat loads revealed the minimum thermal resistance (i.e., the optimum thermosyphon performance) to be 0.03K/W on the boiling side.