To design co-digestion systems, most of the designers consider that the methane production will be equal to 80% of the weighted sum of the biochemichal methanogenic potentials (BMPs) of substrates. However, interactions between substrates can influence the methane production and are generally not taken into account. The objectives of this paper are: (1) the identification of the effect of interactions between substrates on the methane production of co-digestion systems and (2) the identification of the control factors of these phenomena. For this purpose, BMP tests were processed with 30 binary mixtures of substrates and the obtained results were compared with the theoretical BMP values of each mixture obtained by the weighted sum of the BMP value of each substrate in monodigestion. No antagonism was identified. However, synergies were identified for co-digestion tests including porcine slurry and bovine slurry. A statistic analysis highlights that these interaction phenomena are correlated with the biochemical characteristics of co-substrates which can induce enzymatic activation phenomena.