Subacute lead exposure has been observed to inhibit the natriuretic response to isotonic saline expansion in adult female rats. Three-week exposure to 0.5% lead acetate in drinking water resulted in a moderately high blood lead concentration of 57 micrograms/100 ml and up to 60% inhibition of the natriuretic response to extracellular volume expansion. This ability of lead to inhibit natriuresis following volume expansion (an induced stress) may be a more sensitive index of lead poisoning than alterations of renal function in nonstressed animals. Lead exposure had no effect on GFR or plasma aldosterone concentrations, and in the presence of large doses of DOCA (a mineralocorticoid) this inhibitory effect of lead was still persistent. Amiloride completely blocked the antinatriuretic effect of lead in volume-expanded lead-poisoned animals, causing a twofold increase in water and electrolyte excretion while having minimal effects on volume-expanded controls. It is concluded that lead interferes with the action of a "third factor," controlling natriuresis.