In patients receiving hemodialysis, it has long been recognized that much more bicarbonate is delivered during treatment than ultimately appears in the blood. To gain insight into this mystery, we developed a model that allows a quantitative analysis of the patient's response to rapid alkalinization during hemodialysis. Our model is unique in that it is based on the distribution of bicarbonate in the extracellular fluid and assesses its removal from this compartment by mobilization of protons (H+ ) from buffers and other sources. The model was used to analyze the pattern of rise in blood bicarbonate concentration ([HCO3- ]), calculated from measurements of pH and PCO2 , in patients receiving standard bicarbonate hemodialysis. Model analysis demonstrated two striking findings: (1) 35% of the bicarbonate added during hemodialysis was due to influx and metabolism of acetate, despite its low concentration in the bath solution, because of the rapidly collapsing gradient for bicarbonate influx. (2) Almost 90% of the bicarbonate delivered to the patients was neutralized by H+ generation. Virtually all the new H+ came from intracellular sources and included both buffering and organic acid production. The small amount of added bicarbonate retained in the extracellular fluid increased blood [HCO3- ], on average, by 6 mEq/L in our patients. Almost all this rise occurred during the first 2 hours. Thereafter, blood [HCO3- ] changed minimally and always remained less than bath [HCO3- ]. This lack of equilibrium was due to the continued production of organic acid. Release of H+ from buffers is a reversible physiological response, restoring body alkali stores. By contrast, organic acid production is an irreversible process during hemodialysis and is metabolically inefficient and potentially catabolic. Our analysis underscores the need to develop new approaches for alkali repletion during hemodialysis that minimize organic acid production.