The aim of this study is to develop a novel milling system using supercritical carbon dioxide (SC-CO₂) for the improvement of dissolution characteristics of water-poorly soluble drugs. SC-CO₂ possesses high potential in the application of nanotechnology, due to the attractive properties of SC-CO₂ fluid such as cheap, inert and non-polluting. In addition, SC-CO₂ has density comparable to a liquid, viscosity similar to a gas, and high diffusion capacity. Most of all, carbon dioxide exists as gas in room temperature and pressure, which enables the removal of fluid instantaneously. In this study, a novel method of milling using SC-CO₂ was proposed to produce fine-drug particles. SC-CO₂ milling was conducted and its performance was compared with the ones by various milling methods such as jet milling, dry milling and wet milling. A comparison on the effect of each milling medium on its milling performance, drug size distribution, and particle morphology was conducted. Operating variables of the SC-CO₂ milling system were also investigated to clarify the factors affecting the milling properties and to improve drug release characteristics of water-poorly soluble drugs.