Mannitol is commonly used as a pharmaceutical excipient for tablets; the most widely used oral dosage form for drug delivery. For tableting, mannitol is provided in two different forms: native crystals and textured particles. In order to optimize its formulation, a good understanding of the mechanical behavior mechanism of mannitol is necessary. Thus, the aim of this study is to evaluate the deformation mechanism of native mannitol crystals presenting different particle sizes. Pharmaco-technical and compression studies were performed using mannitol with different mean diameters (160 µm, 50 µm and 25 µm). Lactose (monohydrate) and microcrystalline cellulose were used as brittle and plastic reference materials, respectively. Tableting tests and mathematical models, HECKEL and WALKER, were used to study the deformation mechanism of mannitol (β). Mean Yield Pressure (Py) and WALKER coefficient (W) values showed that the studied crystalline mannitol presents a deformation mechanism close to brittle material. A particle-size analyzer was used at different pulverization pressures to show the high sensibility of the mannitol particles to fragmentation when exposed to high pressures, especially for particles presenting 160 µm size. Scanning Electron Microscopy (SEM) was used to show the fragmentation after high-pressure measurements.