The N-terminus of the atrial natriuretic factor (ANF) prohormone (ie, proANF 1–98) contains two vasodilatory peptides consisting of amino acids (aa): aa 1–30 (ie, proANF 1–30) and aa 31–67 (ie, proANF 31–67) of the 126 aa prohormone. The relationship of this N-terminus to the renin-aldosterone axis and blood pressure reduction was investigated in 18 obese subjects (5 hypertensive and 13 normotensive) placed on a 12-week, low sodium (40 mmol), weight reducing diet. The N-terminus of the ANF prohormone and proANF 31–67, which circulates as a distinct entity after being proteolytically cleaved from the N-terminus, were significantly (p < 0.001) higher (767 ± 1.01 and 816 ± 135 fmol/ml) in the obese hypertensive group compared with the obese normotensive group (377 ± 24 and 356 ± 17 fmol/ml, respectively) prior to beginning the weight reduction program. There was a dramatic fall in the N-terminus and in proANF 31–67 after 1 week of weight reduction in both obese groups, which correlated with the decrease in mean arterial pressure during the first week and throughout the 12 weeks of weight reduction (r = .54, p < 0.001 and r = .59, p < 0.001, respectively). ProANF 1–98 had a significant (p < 0.01) inverse correlation with plasma renin in both obese groups. ProANF 31–67, likewise, had an inverse correlation with plasma renin in the hypertensive (p < 0.002), as well as the normotensive (p < 0.03) subjects. ProANF 31–67 did not significantly correlate with aldosterone in either group. ProANF 1–98 had an inverse correlation with aldosterone only in the normotensive group (r = .33, p < 0.01), but not in the hypertensive group. These results demonstrate that weight loss while ingesting a controlled low sodium diet is accompanied by changes in the N-terminus of the ANF prohormone and proANF 31–67, which correlate with changes in blood pressure and inversely correlate with changes in plasma renin activity (PRA). ProANF 1–98 and proANF 31–67 did not correlate with plasma aldosterone concentration in either group, as ANF has been shown to do previously. These findings reflect recent in vitro data that proANF 1–30 and proANF 31–67 have different mechanisms of action at the cellular level because they do not inhibit angiotensin II-stimulated aldosterone production while ANF does inhibit this secretion.