AbstractS‐8666, a newly developed antihypertensive uricosuric diuretic, possesses an asymmetric carbon and exists as a racemic mixture. The enantioselectivity of S‐8666 in natriuresis and the renal excretory mechanisms of the S‐8666 enantiomers were examined. Dose‐dependent natriuresis of the S‐(−)‐enantiomer was observed in male Sprague‐Dawley rats (3–100 mg/kg, p.o.), female Slc:ddy mice (3–300 mg/kg, p.o.) and male NIBS Japan white rabbits (1–10 mg/kg, i.v.). The R‐(+)‐enantiomer produced no significant change in sodium excretion within dose ranges of 100–200 mg/kg p.o. for rats, 3–300 mg/kg p.o. for mice, and 10 mg/kg i.v. for rabits. The (−)‐enantiomer and racemic S‐8666 showed a high‐ceiling property like that of furosemide and unlike that of trichlormethiazide. Plasma protein binding of S‐8666 was over 95% in rabbits and 73% in beagle dogs. In rabbits, both enantiomers of S‐8666 were secreted equally from the proximal tubule; however, only the (−)‐enantiomer of S‐8666 showed diuresis in a stop‐flow pattern. In beagle dogs, secretion of racemic S‐8666 occurred from the proximal tubule and could be inhibited by probenecid. The renal excretion of S‐8666 was largely the result of tubular excretion in rabbits whereas in beagle dogs, some glomerular filtration was also involved in urinary excretion. In conclusion, S‐8666 shows enantioselectivity in natriuresis. Both enantiomers of S‐8666 are excreted mostly by the organic acid transport system in the proximal tubule, but only the (−)‐enantiomer of S