Various studies point to a role of the renal prostaglandin (PG) system in the regulation of renal NaCl excretion. In the present experiments, distal delivery of proximal tubular fluid (DD) [(CH2O+Ccl)/GFR×100] and distal fractional chloride absorption (DFAC1) [CH2O/(CH2O+Cα)] were studied in 6 healthy volunteers undergoing sustained water diuresis. Studies of renal function were performed during intravenous infusion of hypotonic (0.45%) saline and during additional treatment with indomethacin, furosemide and furosemide plus indomethacin. Hypotonic saline was infused at increasing rates of 0.09, 0.18, and 0.36ml min-1 kg-1 body weight each for a 45-min period. DD over all three clearance periods averaged 8.27 + 0.71 ml min-1 100 ml-1 glomerular filtration rate (GFR) during saline infusion alone and was unchanged by indomethacin (8.09 ± 0.63 ml min-1100 ml-1 GFR).DFAC1 averaged 0.79 + 0.02 during saline and significantly increased to 0.87 + 0.01 (p < 0.002) during concomitant indomethacin treatment. Increased NaCl absorption in the diluting segment during indomethacin was paralleled by a decrease in urinary excretion of chloride (UC1V) from 221 + 29 during control to 124 ± 19 µEq/min (p < 0.025) and in urinary excretion of PGE2 (UPGE2V) from 1.45 + 0.12 to 0.51 + 0.09 pmol/min (p < 0.025). Furosemide increased UPGE2V to 2.94 + 0.34 pmol/min (p < 0.05) and UC1V to 2,590 + 128 µEq/min (p < 0.001). This effect was associated with an increase in DD to 26.70 + 1.33 ml min-1 100 ml”1 GFR (p < 0.001) and a decrease in DFACl to 0.19 ± 0.02 (p < 0.001). Neither DD and DFACl nor UClV were altered during furosemide+indomethacin as compared to furosemide in spite of a marked suppression of UPGE2V to 0.56 ± 0.13 pmol/min. Our results support the concept that renal PG participate in the regulation of NaCl absorption in the diluting segments of the nephron. Furthermore, the tubular effects of furosemide appear not to be mediated by the PG system.