The purpose of the current paper is to investigate the Cynara cardunculus (cardoon)/lignite co-firing concept at a 10% biomass thermal share for a 330 MW_e pulverized fuel plant in Northern Greece. Two main cases are considered: (A) co-milling of pelletized biomass with lignite and (B) milling of balled and/or shredded material in dedicated biomass mills. A CFD model for plant simulation is developed taking into account the particularities of co-firing operation, in particular the non-spherical form of the biomass particle and its effect on the drag coefficient, devolatilization and combustion rates. Simulations are performed for the reference case of lignite-firing, which show good agreement with plant operational data, and for the two co-firing cases. Further subdivision of the co-firing cases is based on the biomass particle size and injection point in the furnace. In most co-firing cases, CFD results indicate that the substitution of lignite with biomass has minimal impact on the plant operational parameters as well as the potential for NO_x reductions. Increased unburnt losses in the fly and bottom ash can be expected when large biomass particles are combusted; the best scenario appears to be the separate milling of biomass and its injection in the vapour burners. Economic evaluation of the two cases also favours the dedicated milling system, despite its higher investment cost, due to the lower fuel cost of non-pelletized biomass. The co-firing concept appears to be highly profitable for the plant operator and further optimisation of the combustion process can be suggested by the installation of dedicated biomass burners.