Hyperkalemia in hemodialysis patients is associated with high mortality, but prescription of low dialysate potassium concentrations to decrease serum potassium levels is associated with a high incidence of sudden cardiac arrest or sudden death. Improved clinical outcomes for these patients may be possible if rapid and substantial intradialysis decreases in serum potassium concentration can be avoided while maintaining adequate potassium removal. Data from kinetic modeling sessions during the HEMO Study of the dependence of serum potassium concentration on time during hemodialysis treatments and 30 minutes postdialysis were evaluated using a pseudo one-compartment model. Kinetic estimates of potassium mobilization clearance (KM) and predialysis central distribution volume (Vpre) were determined in 551 hemodialysis patients. The studied patients were 58.8 ± 14.4 years of age with predialysis body weight of 72.1 ± 15.1 kg; 306 (55.4%) of the patients were female and 337 (61.2%) were black. KM and Vpre for all patients were non-normally distributed with values of 158 (111, 235) (median [interquartile range]) mL/min and 15.6 (11.4, 22.8) L, respectively. KM was independent of dialysate potassium concentration (P > 0.2), but Vpre was lower at higher dialysate potassium concentration (R = −0.188, P < 0.001). For patients with dialysate potassium concentration between 1.6 and 2.5 mEq/L (N = 437), multiple linear regression of KM and Vpre demonstrated positive association with predialysis body weight and negative association with predialysis serum potassium concentration. Potassium kinetics during hemodialysis can be described using a pseudo one-compartment model.