Some fatty acids are potent inhibitors of angiotensin binding and aldosterone production in adrenal glomerulosa cells and thereby may be involved in regulating salt and water balance. To study the possible regulation of fatty acids by salt, we measured the levels of unesterified fatty acids in plasma from patients subjected to extremes of dietary salt intake and saline infusion. Insulin and catecholamines, two known regulators of plasma fatty acids, also were measured. Infusion of 2 l saline over 4 hours caused the levels of most unesterified fatty acids to rise. Total unesterified fatty acids rose 60-100%. A high salt diet caused a smaller rise in total unesterified fatty acids (approximately 33%). In both instances, oleic and palmitoleic acids showed the greatest proportionate increases, whereas stearic acid was relatively unaffected. When salt loads were administered by either intravenous or dietary routes, plasma insulin levels fell by approximately 50%. Plasma norepinephrine increased after saline infusion but not during a high salt diet. Postsaline levels of fatty acids correlated inversely with postsaline levels of aldosterone, supporting a possible role for fatty acids as physiological regulators of the adrenal glomerulosa. A rise in plasma fatty acids and fall in insulin in response to salt loads could act in concert to increase sodium excretion, constituting a physiological mechanism contributing to salt and water balance.