The correction of uremic acidosis is one of the goals of hemodialysis; however, despite acceptable hemodialysis protocols, metabolic acidosis remains a common problem. The prevalence of acidosis and significance of factors affecting bicarbonate flux during hemodialysis were studied. A cohort of 70 stable patients receiving high-efficiency hemodialysis for at least 4 months was studied prospectively over a 1-year period. Twenty patients (28%) had a mean predialysis serum bicarbonate of less than 21 mEq/L. The patients with or without metabolic acidosis had similar mean net ultrafiltration and percent ultrafiltration, but acidotic patients had a higher percent increase in bicarbonate during hemodialysis (35 +/- 12 versus 27 +/- 10 [p = 0.008]). The latter suggests an increased net daily acid gain in patients with metabolic acidosis (1.19 +/- 0.32 mEq/kg versus 1.05 +/- 0.35 mEq/kg [p = 0.04]). A review of factors affecting intradialytic bicarbonate gain showed that predialysis serum bicarbonate (diffusive gradient) was the most significant with a demonstrated linear relationship between these two variables (R2 0.51). The role of dialysance and blood flow, assessed together using percent urea reduction, was minor as was the effect of ultrafiltration. At our level of dialysis delivery, prevalence of metabolic acidosis is low, and dialysis-related factors do not contribute to the persistence of metabolic acidosis. Net daily acid gain was higher in acidotic patients and accounts for the long-term maintenance of metabolic acidosis. For individual dialysis treatments, the diffusive gradient is the most important determinant of bicarbonate gain, with only a minor role being demonstrated for percent urea reduction and ultrafiltration rate.