The factors that mediate the increases in salt sensitivity of blood pressure with age remain to be clarified. The present study investigated (i) the effects of high NaCl intake on two Na pump inhibitors, endogenous ouabain (EO) and marinobufagenin (MBG) in middle-aged and older normotensive Caucasian women; and (ii) whether individual differences in EO and MBG are linked to variations in sodium excretion or salt sensitivity. A change from six days of a lower (0.7 mmol/kg/day) to six days of a higher (4 mmol/kg/day) NaCl diet elicited a sustained increase in MBG excretion that directly correlated with an increase in the fractional Na excretion, and was inversely related to age, and to an age-dependent increase in salt-sensitivity. In contrast, EO excretion increased only transiently in response to NaCl loading, and did not vary with age, or correlate with fractional Na excretion or salt sensitivity. A positive correlation of both plasma and urine levels of EO and MBG during salt loading may indicate a casual link between two Na pump inhibitors in response to NaCl loading, as observed in animal models. A linear mixed-effects model demonstrated that age, dietary NaCl, renal MBG excretion, and body mass index were each independently associated with systolic blood pressure. Thus, a sustained increase in MBG in response to acutely elevated dietary NaCl is inversely linked to salt-sensitivity in normotensive middle-aged and older women; and a relative failure of MBG elaboration by these older persons may be involved in the increased salt sensitivity with advancing age.