Large-pore mesoporous SBA-15-type and FDU-12-type silicas have been synthesized and functionalized with perfluorosulfonic acidic Nafion resin using a postsynthetic impregnation method. The remarkable physicochemical properties of these large-pore ordered silicas (high surface area, open structure, large pore size, and thermal stability) make them particularly attractive for the immobilization of strongly acidic perfluorosulfonic sites. The loading of Nafion resin was 15 wt % and the impregnation method provided ca. 100% yield of incorporation. The synthesized Nafion-modified materials were evaluated in the liquid-phase acylation of anisole with acetic anhydride, and compared with other commercially available catalysts (Nafion NR50, Nafion SAC-13, and zeolite ZSM5). The prepared catalysts provided much higher activities than the commercial samples, the performance of the material Nafion(15)/LP-FDU-12 being especially outstanding. This material takes advantage from both a large-pore size and 3D interconnected cubic pore structure, facilitating the diffusion of chemicals.