Vapor-phase aldol condensation of methyl acetate with formaldehyde over vanadium phosphorus oxide (VPO) deposited on SiO2, TiO2, ZrO2, Nb2O5, Sb2O3, gamma-Al2O3, and n-gamma-Al2O3 (gamma-Al2O3 treated with H3PO4) for methyl acrylate production was developed. The VPO/n-gamma-Al2O3 was found to have the best performance based on the evaluated experiments in a fixed-bed reactor. The physicochemical properties of the catalysts were investigated by different characterization methods such as the Brunauer Emmett Teller method, X-ray diffraction, scanning electron microscopy, transmission electron microscopy, H-2 temperature programmed reduction, Fourier transfrom infrared spectroscopy, and NH3- and CO2-temperature programmed desorption. The influence of P-OH intensity and acid strength on activity was obtained through systematic studies over the formation process of VPO phases and the acidity distribution. Preparation and reaction parameters were investigated and optimized.