Pt/xNb2O5/(100-x)Al2O3 (x = 0, 5, 20, 100, wt.%) catalysts were tested on the gas phase hydrodeoxygenation (HDO) of guaiacol (2-methoxyphenol, C7H8O2), model compound representative of the lignin-derived portion of the bio-oil produced after pyrolysis or HTL. The physicochemical properties of the catalysts were analyzed by XRD, N2 physisorption, CO chemisorption, and temperature programmed desorption of isopropylamine. The catalytic performances were evaluated in a continuous flow system at atmospheric pressure with the aim of reducing the oxygen content of the guaiacol molecule as an upgrading step of the biomass processing. The influence of H2 partial pressure, temperature, space velocity, and pure supports performance on both activity and selectivity was determined. The Pt/Nb2O5 catalyst exhibited superior oxygen removal. Niobia addition enhanced the selectivity towards phenol while Pt/Al2O3 formed mainly catechol. The interaction between Pt and NbOx species probably enables oxophilic sites formation which enhances DDO reaction towards phenol formation and less deactivation even at low hydrogen content.