The role of nephron loss, extracellular fluid volume (ECFV) expansion and body potassium stores on bicarbonate reabsorption in chronic renal failure (CRF) was evaluated. In 17 CRF and 3 control subjects, tubular HCO3 reabsorption was studied by HCO3 1M titration technique; ECFV (22Na space at 4th hour) and cell K content (muscle biopsy) were also determined. Nephron loss per se does not cause any change of HCO3 reabsorption rate per unit GFR. With ECFV expansion induced by HCO3 infusion, a Tm HCO3 is rapidly reached only in controls and in CRF patients showing a significant basal ECFV expansion. In these subjects reabsorbed HCO3/Na ratio is constant, suggesting that under these conditions, HCO3 reabsorption depends on the same mechanisms that control Na reabsorption. In cell K depleted CRF patients, HCO3 reabsorption rises more than in controls and no Tm HCO3 is detected, at least within the limits of isotonic ECFV expansion induced by titration; in these subjects HCO3 reabsorption does not appear to be limited by natriuretic factors. In CRF subjects with normal ECFV and cell K, there is a greater HCO3 tolerance to ECFV expansion induced by titration technique than in controls.