Digoxin-like immunoreactive substances, which cross-react with digoxin antibody, have been found to have natriuretic effect and Na+,K+-ATPase inhibitory effect. The role of digoxin-like immunoreactive substances in chronic liver disease was studied by radioimmunoassay in 63 serum and 60 urine samples from 58 patients with chronic liver disease and compared with 16 controls. Although the mean serum digoxin-like immunoreactive substances level of compensated chronic liver disease patients (0.06 +/- 0.05 ng per ml, p less than 0.01) was higher than that of controls (0.02 +/- 0.03 ng per ml), only four patients had serum digoxin-like immunoreactive substances higher than 0.10 ng per ml. Mean serum digoxin-like immunoreactive substances level was much higher in patients with decompensated chronic liver disease who had ascites (0.32 +/- 0.17 ng per ml, p less than 0.001), hepatorenal syndrome (0.57 +/- 0.20 ng per ml, p less than 0.001) and hepatic encephalopathy (0.43 +/- 0.20 ng per ml, p less than 0.001). Five patients with recent variceal hemorrhage requiring transfusions and saline infusion had significantly increased serum digoxin-like immunoreactive substances (mean: 0.16 +/- 0.06 ng per ml, p less than 0.001) before the development of clinically detectable ascites.(ABSTRACT TRUNCATED AT 250 WORDS)