To evaluate determinants of elevated plasma atrial natriuretic factor levels in patients with hypertension, immunoreactive plasma atrial natriuretic factor in 54 normal subjects and 40 untreated hypertensive patients was compared with echocardiographic measurements of cardiac size, function and systemic hemodynamics. In normal subjects, plasma atrial natriuretic factor was related to age, systolic blood pressure and left atrial and ventricular chamber sizes, but only age and ventricular size were independent predictors. In untreated hypertensive patients, atrial natriuretic factor was directly related to age, atrial size, systolic pressure, peripheral resistance and ventricular systolic performance; age, atrial size and peripheral resistance were independent predictors. Eight patients with elevated atrial natriuretic factor values (greater than 25 fmol/ml) were significantly (p less than 0.01) older and had greater atrial and ventricular size and higher systolic pressure and function than normal subjects or patients with normal natriuretic factor levels. Plasma atrial natriuretic factor was inversely related to peak diastolic filling rate in normal subjects (r = -0.59; p less than 0.001), whereas it was positively related to the proportional contribution of atrial systole to left ventricular filling in hypertensive patients (r = 0.77; p less than 0.001). These findings suggest that in normal subjects, impairment of ventricular relaxation with age may contribute to atrial natriuretic factor secretion by increasing left atrial afterload; the correlation with left ventricular size may reflect physiologic fluctuations in plasma volume. In patients with uncomplicated hypertension, left atrial enlargement and consequent stronger atrial contraction contributed to increased atrial natriuretic factor release, whereas no independent relation existed with left ventricular hypertrophy or systolic function. Because ventricular relaxation was normal and ventricular size and systolic performance were increased in hypertensive patients with high atrial natriuretic factor levels, the observed increase in left atrial size and atrial contribution to ventricular filling might reflect a primary increase in venous return in this subset of hypertensive patients.