Sertraline hydrochloride (designated as sertraline from now on) is an antidepressive drug with unpleasant effects in the gastric tract. Therefore, improved means of delivery allowing for a more controlled and efficient release were looked for. Two different porous materials, montmorillonite-K10 and MCM-41, were chosen as hosts. The drug was intercalated in the interlayer spacing of the clay by cation exchange and was loaded inside the MCM-41 channels by pore volume impregnation means. Spectroscopic evidence (UV/vis, FTIR, powder X-ray diffraction (XRD) and (13)C CP/MAS and (29)Si CP/MAS and MAS solid-state NMR), as well as elemental analysis, complemented by DFT calculations, demonstrated the presence of sertraline in the composite materials. The release processes were monitored under in vitro conditions using a simulated body fluid. The release profile from the clay is fast, indicating that a concentration peak is reached in a short period of time, while the release profile from MCM is slower but lasts longer. These differences are discussed on the basis of different therapeutic indications for both materials.