Digoxin concentrations were measured in serum samples from 102 patients with renal impairment who were receiving digoxin therapy. Many patients had values that differed widely on several currently available immunoassays, with differences as great as 2.9 ng/mL. In contrast, patients with normal renal function who were receiving digoxin had few discrepant results, with the largest difference being 0.5 ng/mL. We also assayed serum samples from 54 patients with renal impairment not on digoxin therapy and found that more than 60% of these digoxin-free patients had false-positive digoxin values on most assays. Our data suggest that a substance with digoxin-like immunoactivity is present in many patients with renal insufficiency. This substance may seriously compromise the accuracy and interpretation of digoxin concentration measurements.