Hemodiafiltration (HDF) is the strategy enabling the high potential of hydraulic and solute permeability of synthetic membranes to be most properly exploited. On-line production of unlimited amount of sterile dialysate at low cost has favored its extensive diffusion in the recent years. However, to achieve the most efficient convective transport, ultrafiltration rate must be forced towards its physical limits, paying attention to the safety of the patient and to the integrity of the system. The infusion mode variably influences the dialyzer performance and the efficiency of the technique. With respect to standard and high-flux hemodialysis (HD), increased removal of solutes in the small and middle molecular weight range was reported with on-line HDF in several recent studies. Some of these compounds have a pathogenic role or are markers of the most frequent long-term complications and causes of death in HD patients, such as dialysis related amyloidosis, cardiovascular disease, inflammation and malnutrition. Even in the absence of definite evidence, coming from large data base studies, there are strong indications to advise the use of this dialytic strategy, which combines the benefits of the high biocompatibility of the membrane and the sterile dialysis fluid with increased removal by convection of middle-molecular uremic toxins. A new mode of infusion in on-line HDF--the mixed infusion mode--is here described, which is able to achieve and maintain the maximum possible water and solute removal during the sessions through a feedback control of the transmembrane pressure.