In man the first days of fasting are characterized by enhanced natriuresis despite an increase in aldosterone secretion. Therefore the possibility of a decreased renal tubular sensitivity to this hormone was considered. The response to aldosterone infused before a fast and again on day 4 of fasting was evaluated in 12 starving obese women in terms of urinary sodium, chloride and potassium excretion. The data were compared to those obtained from 20 untreated starving obese women. In addition, salivary flow and sodium output were measured before and after aldosterone infusion in 4 out of the 12 patients treated. The involvement of aldosterone in the mechanism of fasting natriuresis and glucose-induced sodium retention was evaluated by means of spironolactone treatment (Aldactone A; 300 mg/day p.o.) on days 6 to 8 of the fast, with an oral glucose load (100 g) on day 7. Aldosterone infused on day 4 of the fast caused on average only 40% of the antinatriuretic effect it achieved before the fast. On the other hand even before aldosterone infusion, salivary sodium output was markedly reduced during the fast to levels comparable to those observed after aldosterone treatment in the pre-fast period. Furthermore, spironolactone administration on day 6 of the fast was associated with a prompt and marked increase in natriuresis. These 3 sets of facts indicate a definite biological activity of aldosterone during the initial phase of fasting with factor(s) interfering at the renal level with the normal expression of the hormonal action on sodium balance. There was still a distinct antinatiuretic effect of glucose in the presence of spironolactone, but less pronounced than when glucose was administered alone. The well-documented hyperaldosteronism of a total fast may represent a compensatory mechanism to decrease sodium loss at the end of a week-long fast. In addition a marked sodium-retaining effect of glucose can be demonstrated after aldosterone action is blocked by spironolactone. This provides another indication that glucose stimulates sodium retention through mechanism(s) which do not involve aldosterone.