Hemodialysis constitutes the lifeline of patients with end stage renal disease, yet the parameters that affect hemodialyzer performance remain incompletely understood. We developed a computational model of mass transfer and solute transport in a hollow-fiber dialyzer to gain greater insight into the determinant factors. The model predicts fluid velocity, pressure, and solute concentration profiles for given geometric characteristics, membrane transport properties, and inlet conditions. We examined the impact of transport and structural parameters on uremic solute clearance by varying parameter values within the constraints of standard clinical practice. The model was validated by comparison with published experimental data. Our results suggest solute clearance can be significantly altered by changes in blood and dialysate flow rates, fiber radius and length, and net ultrafiltration rate. Our model further suggests that the main determinant of the clearance of unreactive solutes is their diffusive permeability. The clearance of protein-bound toxins is also strongly determined by blood hematocrit and plasma protein concentrations. Results from this model may serve to optimize hemodialyzer operating conditions in clinical practice to achieve better clearance of pathogenic uremic solutes.