Thiazide diuretics reach their presumed intraluminal site of action by active transport at the organic acid secretory site of the proximal tubule. Probenecid competes for this transport and might therefore affect the diuresis induced by thiazide at that site. Doses of 500 mg and 1 gm of chlorothiazide (CTZ) intravenously to 5 volunteers with probenecid pretreatment increased 8-hr rates of excretion of sodium and urine over that without probenecid. Eight-hour excretion of sodium after administering 500 mg of CTZ was 147 +/- 7.5 mEq and 257.9 +/- 16.4 mEq after CTZ with probenecid (p less than 0.0005). The volume of urine after CTZ was 728 +/- 37 ml and 1,886 +/- 301 ml after CTZ with probenecid (p less than 0.001). This increase was associated with prolongation of CTZ diuresis rather than increase in intensity. These results are consistent with CTZ reaching its site of action from the peritubular side or that prolonged exposure of the lumen to lesser amounts of filtered CTZ causes a greater overall effect.