Abnormalities of intracellular calcium homeostasis and sodium-proton exchange have been implicated in the pathophysiology of essential hypertension. To further define the nature of cytosolic calcium abnormalities and whether they relate to increased sodium-proton exchange in hypertension, we have studied peripheral lymphocytes from normotensive and hypertensive subjects. Lymphocyte cytosolic calcium was significantly increased (P < .01) in hypertensive compared with normotensive subjects while consuming a high salt diet. Using maximum likelihood analysis, we found that cytosolic calcium levels in our study population were not normally distributed and observed three modes (P < .02). The means of the first mode and the two upper modes were separated (+/-2 SD) at a cytosolic calcium level of 120 nmol/L. We conducted further analysis in the subgroups with cytosolic calcium levels > 120 nmol/L or < 120 nmol/L. The majority of the normotensive subjects (86%) and half of the hypertensive subjects (52%) had levels < 120 nmol/L. Clinical characteristics of the two subgroups did not differ. Subjects with levels < 120 nmol/L had a rise in cytosolic calcium when changed to a low salt diet; those with levels > 120 nmol/L did not show a change in cytosolic calcium but their blood pressure fell significantly with salt restriction. Hypertensive subjects also had increased sodium-proton exchange activity compared with normotensive subjects when both groups were studied in a high salt balance. A positive correlation between sodium-proton exchange and cytosolic calcium was observed in subjects with levels < 120 nmol/L. There was insufficient power to draw conclusions on this relationship in subjects with levels > 120 nmol/L. Thus, many hypertensive subjects have increased cytosolic calcium, but this abnormality is not associated with sodium-proton exchange activity in all individuals. The salt-induced change in cytosolic calcium in subjects with levels < 120 nmol/L and its link to sodium-proton exchange suggest regulation by factors involved in salt-volume homeostasis. Individuals with cytosolic calcium > 120 nmol/L, most of whom were hypertensive, may have abnormalities in this regulation, contributing to hypertension.