The relationship between renal tubular secretion and saluretic effects of two thiazides (chlorothiazide and hydrochlorothiazide) and clopamide was studied using a modified Sperber technique. The distribution of carbonic anhydrase in the avian kidney was studied by a histochemical method. The modified Sperber technique allows an absolute estimation of the tubular excretion efficiency of a substance, as determined by its True Tubular Excretion Fraction (TTEF). The TTEF values were for chlorothiazide 59%, hydrochlorothiazide 22% and clopamide 10%. Thus, they were all actively secreted by renal tubular cells; most likely through organic anion transport since novobiocin markedly reduced the TTEF values. After infusion of the diuretics into the renal portal system on one side there was only a small ipsilateral excess natriuresis and chloruresis, in spite of their different tubular excretion efficiencies. For hydrochlorothiazide, and especially for chlorothiazide the saluretic effect therefore appears to be largely independent of the tubular fluid concentration of the diuretic and primarily evoked from the peritubular side of the avian nephron. This is a sharp contrast to the primarily luminally induced saluretic effects of furosemide, ethacrynic acid and piretanide. Only chlorothiazide caused an ipsilateral excess excretion of potassium and bicarbonate, probably due to inhibition of carbonic anhydrase since similar effects were seen after acetazolamide. This effect was coupled to tubular secretion of the diuretic, and probably reflects an inhibition of carbonic anhydrase in cortical distal tubules, where the enzyme is present in the apical region of most cells and could be reached by chlorothiazide present in the tubular fluid.