Stability of predialysis sodium “setpoint” has not been validated in quotidian dialysis patients. We performed a retrospective review of our home hemodialysis program, to determine the effect of transitioning from conventional thrice weekly to home hemodialysis modalities differing in dialysis duration and frequency (n = 87). Mean sodium setpoint remained constant in patients who went home on intermittent hemodialysis, but decreased by 100 days in frequent nocturnal home hemodialysis (FNHD) (140.5–137.1 mM, p = 0.001) and short hours daily hemodialysis (SHD) (140.2–138.7 mM, p = 0.019) patients with a pretransition setpoint greater than dialysate sodium of 140 mM. Slope of predialysis sodium concentration within the first 100 days post-transition (M100) was less than zero in SHD (95% confidence interval [CI], −0.0081 to −0.0351 mM/day) and FNHD (95% CI, −0.0209 to −0.0695 mM/day) patients who started with a pretransition setpoint greater than dialysate sodium concentration of 140 mM. Change in sodium setpoint (SP) was predicted by dialysis frequency and the difference between dialysate sodium concentration and the pretransition predialysis sodium concentration (R2 = 35.4%, adjusted R2 = 33.8%, p < 0.001). Thus, personalizing dialysate sodium concentrations may be associated with a decrease in SP, which is independently associated with increased mortality. Further research is required to determine whether intentional increases in the SP could improve cardiovascular and all-cause mortality.