Two digoxin-like immunoreactive substances (DLIS 1 and DLIS-2) were isolated from human plasma by ultrafiltration, alkaline solvent extraction, and HPLC. Both inhibit canine Na, K-ATPase and cross-react with anti-digoxin antibodies. Their UV spectra are similar, with absorption peaks at 190 and 220 nm. FAB mass spectral analysis of both compounds yield a single dominant (M+H)+ component at m/z 532 otherwise, the fragmentation patterns are slightly different. The spectral data are consistent with the postulate that these compounds are related. Their identity as the natriuretic hormone is being investigated.