Pressure-dependent elastic behavior and chemical reaction of natural sepiolite (Mg8Si12O30(OH)4·12H2O) was studied under two different pressure-transmitting medium (PTM) conditions using synchrotron X-ray powder diffraction. Under non pore-penetrating silicone oil PTM, we observed that the b-axis length increases up to ca. 3.6 GPa, marking an anisotropic compression region with negative linear compressibility of βb= -0.0012 GPa-1, which then decreases at 7.7 GPa. Under pore-penetrating water PTM, the anisotropic compression behavior is enhanced with doubled negative linear compressibility of βb= -0.0025 GPa-1 up to 3.2 GPa, where transformation into stevensite is observed upon ex-situ temperature treatment at 280 ℃ as confirmed via XRD and SEM. Derived bulk moduli (K0) and linear compressibilities (β) were compared to other structurally and chemically related minerals.