The purpose of this study is to compare the effects of extracellular volume expansion (ECVE) and acetazolamide (ACTZ) on the transport of sodium in the diluting segment in man. All studies were performed at the peak of sustained oral water diuresis (Uosm. less than 75 mOsm. per kilogram). Distal delivery was estimated by the rate of urine flow and distal sodium reabsorption was approximated by the generation of free water. Free water clearance for given rates of distal delivery expressed as V(range 10 to 35 ml. per minute) was significantly lower and the clearance of sodium higher in the ACTZ group as compared with subjects with ECVE. However when CH2O was plotted against distal delivery expressed as CC1 + CH2O, no difference was detected between ACTZ and ECVE studies. We interpret these findings as suggesting that ACTZ does not have a direct inhibitory influence on the NaCl pump at the diluting site. Rather, the lowering of CH2O/V following ACTZ is due to the flooding of the diluting site with the poorly reabsorbable bicarbonate ion. Thus, the proximal action of ACTZ, which initiates urinary bicarbonate loss results secondarily in an apparent interference with the diluting mechanism in man.