Clearances obtained during clinical hemodialysis are smaller than those predicted from in vitro measurements obtained with cell and protein free solutions, although the exact cause of this clearance reduction is unclear. This study examined the specific effects of blood contact on the in vitro clearance of urea, vitamin B12, and polydispersed dextrans using cuprophan, AN69, and polysulfone dialyzers. Blood contact caused a significant reduction in solute clearance, with the actual reduction a complex function of dialyzer type, solute, and ultrafiltration rate. The reduction in urea clearance at zero ultrafiltration ranged from 9% (polysulfone dialyzer) to 19% (cuprophan dialyzer). The percent reduction in clearance increased with increasing solute molecular weight for AN69 and polysulfone dialyzers, with the clearance after blood contact essentially zero for the larger dextrans (molecular weight > 15,000). The relative contributions of fiber blockage and membrane transport were examined using a theoretical model for solute transport during dialysis, with the membrane properties evaluated from independent experiments. The in vitro clearance data obtained in this study were in agreement with clinical observations, suggesting that differences between in vivo and in vitro clearances are largely the result of blood-membrane interactions (i.e., fiber blockage and reduced membrane transport properties).