A study was carried out over 2 years (2008/2009 and 2009/2010) in Greece, in order to evaluate the weed control using REDUCED rates of the HERBICIDE mesosulfuron-methyl+iodosulfuron-methyl-sodium of four major weeds (Avena sterilis, Phalaris minor, Papaver rhoeas and Sinapis arvensis), grain yield and yield components of five wheat cultivars (Bob, Cosmodur, Meridiano, Quadrato and Simeto). The results indicated a significant differentiation between the several wheat cultivars regarding their weed competitive ability, in terms of dry biomass and seed production. In the case of cultivars such as Simeto the efficacy of 50% reduction of the HERBICIDE recommended rate on wild oat remained high, since it resulted to a reduction of biomass and seed production up to 81 and 98% compared with the untreated plots. In most cultivars studied, the reduction of the HERBICIDE rates by 25 to 50% resulted to a no significant reduction of grain yield compared to the recommended rate. The study revealed that some wheat cultivars with enhancing weed competitiveness can improve the efficacy of REDUCED HERBICIDE rates. Consequently, sustainable cropping systems could be further developed through the integration of such agronomic practices, while in parallel, care on the threat of HERBICIDE resistance development should be also taken.