A digoxin-like immunoreactive substance (DLIS) has been described in the sera of patients with renal impairment. To further investigate this problem, we measured digoxin in 50 patients with elevated serum creatinine using 4 commercial digoxin immunoassay kits (3 radioimunoassay methods and 1 fluorescence polarization immunoassay technique). Ten of the patients were receiving digoxin therapeutically, while the remainder were not receiving the drug. Two of the radioimmunoassay kits detected low amounts of DLIS in 23% of the subjects not receiving digoxin, the highest level being 0.5 nmol/l. No DLIS was detected by the other radioimmunoassay kit or by the fluorescence polarization technique. The majority of renal patients receiving digoxin had similar results by all 4 methods, although 2 patients differed by 0.6 nmol/l as measured by 2 of the radioimmunoassay kits. We conclude that the extent of interference by DLIS in digoxin immunoassays in patients with renal impairment is not as great as has been previously reported.