The mechanism that sustains chloride-depletion metabolic alkalosis is presumed to be a stimulation of renal acidification, so that the elevated filtered bicarbonate load that attends hyperbicarbonatemia is completely reabsorbed. However, such enhancement of renal bicarbonate reabsorption is not necessary to maintain hyperbicarbonatemia if the filtered bicarbonate load is not increased owing to a concomitant reduction in glomerular filtration rate (GFR). To assess the relative contributions of enhanced renal bicarbonate reabsorption and reduced GFR in the maintenance of chloride-depletion alkalosis in humans, selective hydrochloric acid depletion was induced in five normal subjects. Plasma bicarbonate concentration increased by 27% (25.3 +/- 0.1 to 32.1 +/- 0.3 mEq/liter, P less than 0.005), whereas the rate of renal bicarbonate reabsorption increased by only 17% (2.7 +/- 0.1 to 3.2 +/- 0.2 mEq/min, P less than 0.05) owing to a 10% reduction in GFR (93.2 +/- 4.4 to 84.3 +/- 4.1 ml/min, P less than 0.01). Thus, in chloride-depletion metabolic alkalosis in humans, the increase in plasma bicarbonate concentration is not attended by a commensurate increase in filtered bicarbonate and rate of renal bicarbonate reabsorption. Both a reduction in GFR and an enhancement of renal bicarbonate reabsorption contribute to maintenance of the alkalotic state.