Catalytic dehydration of D-fructose to 5-hydroxymethylfurfural (HMF) was investigated over a series of Nafion-modified mesocellular silica foam (MCF) materials. By using an impregnation method, Nafion resin was highly dispersed in the ultra-large pores of the MCFs. Highly efficient and selective dehydration of D-fructose to HMF was achieved in dimethyl sulfoxide solvent; an 89.3 % HMF yield with 95.0 % selectivity was obtained in the presence of the Nafion(15)/MCF catalyst. The effects of reaction temperature, reaction time, and solvent on the dehydration of D-fructose were systematically investigated. The catalyst could be regenerated through an ion-exchange method and a high yield was retained after being used five times. As a heterogeneous catalytic process, a possible reaction mechanism for the dehydration of D-fructose over Nafion-modified MCF catalysts was proposed.