The main purpose of this study was to validate the use of a simple model for forecasting methane production in co-digestion reactors run semi-continuously using substrate data acquired in batch mode. Firstly, seven solid substrates were characterized individually in successive batches to assess their Biochemical Methane Potential (BMP) and kinetic parameters. Afterwards, eight mixtures of two, three or five substrates were processed in semi-continuous mode at an organic loading rate of 1 g VS L−1 d−1. The experimental methane production was always greater than that calculated from the BMP of each substrate. This result suggested that, endogenous activity needs to be taken into consideration in order to predict total methane production accurately. Near equivalence between experimental and modeled methane production was found after integration in the model of the endogenous activity. The results confirmed the possibility for use of substrate batch data (BMP and kinetics) to predict methane production in semi-continuous operations.