1. Plasma concentrations of human alpha-atrial natriuretic polypeptide (h-alpha ANP) during escape from the effects of mineralocorticoid excess were determined in six healthy volunteers. 2. Escape, as indicated by an abrupt increase in sodium excretion on the third to sixth day of 9 alpha-fludrocortisone acetate administration (0.6 mg/day), was observed in all subjects. 3. The mean plasma h-alpha ANP level was 30.9 +/- SEM 8.8 pmol/l on the control day; it increased exponentially in response to 9 alpha-fludrocortisone acetate administration, reached a significant level (114.0 +/- 22.4 pmol/l, P less than 0.05) on the day before escape and remained elevated during escape. 4. The 24 h creatinine clearance and blood pressure did not change significantly before the escape. Plasma h-alpha ANP increased markedly when the cumulative sodium balance exceeded 220 mmol. 5. These results suggest that h-alpha ANP may play a contributory role in natriuresis and diuresis after mineralocorticoid excess.