The ability of urine extracts to inhibit sodium and potassium–activated ATPase, cross-react with antidigoxin antibodies and induce natriuresis in rats was investigated in 10 healthy subjects, 10 cirrhotic patients without ascites (compensated cirrhotics), 27 nonazotemic cirrhotic patients with ascites and 10 cirrhotic patients with ascites and functional renal failure to assess whether reduced activity of natriuretic hormone contributes to sodium retention in cirrhosis. No significant differences were seen between healthy subjects and compensated cirrhotic patients in any of these parameters (sodium and potassium–activated ATPase inhibition = 178.5 ± 19.8 vs. 247.4 ± 48.7 nmol equivalent of ouabain/day; digoxinlike activity = 43.9 ± 6.1 vs. 48.0 ± 5.6 ng equivalent of digoxin/day; natriuretic activity = 0.36 ± 0.15 vs. 0.63 ± 0.27 μmol/min). Cirrhotic patients with ascites with and without functional renal failure showed significantly higher values of sodium and potassium–activated ATPase inhibition (708.1 ± 94.0 and 529.2 ± 53.9 nmol equivalent of ouabain/day, respectively), digoxinlike activity (136.9 ± 7.2 and 116.3 ± 7.9 ng equivalent of digoxin/day) and natriuretic activity (1.78 ± 0.48 and 1.93 ± 0.37 μmol/min) than healthy subjects and compensated cirrhotic patients. We saw no significant differences between these two groups of cirrhotic patients with ascites with respect to these parameters. In the cirrhotic patients studied, sodium and potassium–activated ATPase inhibition and antidigoxin antibodies directly correlated with the degree of impairment of hepatic and renal function, plasma renin activity and plasma levels of aldosterone and norepinephrine. These results show that natriuretic hormone activity is increased in cirrhotic patients with ascites and suggest that sodium retention in these patients cannot be attributed to a deficiency in this hormone. An alternate explanation, however, is that the increased activity of natriuretic hormone in patients with cirrhosis and ascites, which may represent a compensatory response, is not sufficient to antagonize the renal effects of sodium-retaining forces. (HEPATOLOGY 1990;12:467–475).