A model-based optimisation method for the start-up of anaerobic co-digestion is presented. The algorithm optimises the time evolution of the organic loading rate (OLR), the blends of substrates corresponding to each OLR and the hydraulic retention time (HRT). These parameters are calculated based on the prediction of a dynamic co-digestion model, so as to track the methane production flowrate set as reference. The mixtures of substrates and the OLR are optimised sequentially with linear programming and a direct-search method, respectively. Initially, a simulated case-study (treating blends of gelatine, glycerine, and pig manure) is tested to verify the convergence of the algorithm. Then, two consecutive start-up experiments are performed at lab-scale to validate the proposed optimisation method. Blends of sewage sludge and pig manure are treated in a 14-litre CSTR at loading rates of 1.70-2.43 gVS/L d for 79 and 90 days at mesophilic conditions. The optimisation strategy satisfactorily computes the best OLR, blends and HRT for the entire operations, improving the biogas yield over traditional manual operation. (c) 2021 Elsevier Ltd. All rights reserved.