The presence in plasma extracts of a sodium pump inhibitor with digitalis-like properties was investigated by two complementary tests: decrease in the affinity of ouabain binding to human red blood cells and inhibition of Na+,K+-ATPase. The results of the two methods were correlated (r = 0.76, n = 44, p less than 0.01), suggesting that the same factor may be responsible for both effects. All subjects with elevated values were hypertensive or normotensive and had a family history of hypertension. Forty percent of the subjects in these two groups had high inhibition values. The elevation was significant (p less than 0.01) when compared with values in normotensive subjects with no hypertensive heredity. Increased inhibition was observed in patients taking beta-blocking agents; conversely, diuretics normalized the values. No correlation was found between pump inhibition and age, sex, blood pressure, levels of plasma K+ or Na+, or plasma renin activity. These data show the existence of a sodium pump inhibitor in the plasma of some subjects and point to a possible association with hypertension. They also underline the importance of genetic background and the heterogeneity of essential hypertension.