To assess the biochemical effects of a hemodiafiltration procedure where low-molecular-weight proteins can be removed from the plasma, 7 patients with end-stage renal disease were studied during a 6-month period of high-flux dialysis as well as during a succeeding 6-month period of hemodiafiltration. Distinct changes in the plasma protein composition occurred during the hemodiafiltration period, which cannot be explained solely as a result of molecular-weight-dependent filtration. Low-molecular-weight proteins in the plasma were reduced but losses of larger proteins occurred simultaneously. It is concluded that by increasing the dose of diffusive and convective transport in hemodiafiltration the renal tubular function in the catabolism of low-molecular-weight proteins cannot be replaced. The main obstacle to achieve such a goal appears to be the low selectivity of current high-flux membranes for low-molecular-weight proteins.