Abstract: The object of the present study is the isodesmic reaction of cellobiose (the repeating unit in cellulose) with different kinds of silanes, R-SiH₃, to form silylated cellobiose (Cello-SiH₃) and the corresponding alcohols (R-OH). The size and the chemical reactivity of the substituent R is varied as well as the position where O-silylation at the cellobiose takes place. In contrast to experimental observations where the O6 position is favored for silylation, for the computed reactions, energy differences are smaller than 3 kcal/mol for the different positions at the B3LYP/6-311G* as well as at the B3LYP/6-311+G* level of theory. Depending on the silane, reaction energies in a range from -17 kcal/mol (R=NHSiH₃) and +18 kcal/mol (R=F) have been calculated. In addition, semi-empirical calculations on the PM3 level of theory have been performed. These results are set into contrast with the results derived from DFT calculations to assess whether semi-empirical methods may be useful for the description of larger systems containing silylated cellobiose units. Acknowledgements: The research leading to these results has received funding from the European Community\'s Seventh Framework Programme [FP7/2007–2013] under grant agreement no. 214015 (S.S. and H.M.A.E.) and no. 214653.