As part of a recent research effort aimed at employing mesoporous materials for controlled drug delivery, this paper presents MCM-41 as a carrier for topical application, using Trolox as a model unstable guest molecule. The complexes between Trolox and MCM-41 were prepared by employing different inclusion procedures, varying solvent, method and pretreatment of the silica matrix. The objectives of this study were to determine Trolox loading, analyze its integrity and availability after immobilization on mesoporous silica, evaluate MCM-41 influence on Trolox photodegradation and establish whether the preparation method significantly influences complex properties. The characterization analyses (XRD, TGA, DSC and FTIR) confirmed the hydrogen-bonding interaction and Trolox structure preservation. Gas-volumetric analysis showed a consistent decrease in surface area and in pore volume and diameter with respect to bare MCM-41 indicating that Trolox was mainly located within mesopores. In vitro diffusion tests showed a slower release of Trolox after inclusion in the MCM-41 matrix; at the same time UV irradiation studies highlighted an increased photostability for the complex particularly in O/W emulsion. Moreover the radical scavenging activity of Trolox was maintained after immobilization. In all cases, differences were observed in all tested samples, suggesting that results could be optimized by modifying the inclusion procedure and by improving the guest loading.