The objectives of the present study were to determine whether increased sodium-lithium countertransport is associated with essential hypertension in the general Caucasian population and to determine whether this association is independent of the effects of gender, age, body size, and plasma lipids. We studied 543 men and 589 women from the population of Rochester, Minnesota. Mean sodium-lithium countertransport was higher in hypertensive than in normotensive subjects in men (370±147 [mean±SD] versus 315±110 jtmol/1 red blood cells [RBC]/hr, p<0.001) and in women (339±114 versus 269±92 fimol/l RBC/hr,p<0.001). Interindividual differences in plasma triglycerides, body mass index (wt/[ht]2), and plasma total cholesterol explained 13.0% of sodium-lithium countertransport variation in men (p<0.001) and 20.2% in women (p<0.001). Age did not predict additional sodium-lithium countertransport variation in either gender. Slopes of the regressions of sodium-lithium countertransport on plasma triglycerides, body mass index, and plasma total cholesterol did not differ between diagnostic groups in men (p=03l) or in women (p=0J29). After adjustment to remove sodium-lithium countertransport variation attributable to these covariates, mean sodium-lithium countertransport remained significantly higher in hypertensive than in normotensive subjects in men (354±139 versus 319±104 /i.mol/1 RBC/hr, p<0.01) and in women (311 ±103 versus 278±83 /imol/1 RBC/hr, p<0.01). These findings in a large sample from Rochester, Minnesota, support the conclusions that increased sodium-lithium countertransport is associated with essential hypertension in the general Caucasian population and that this association is independent of the effects of gender, age, body size, and plasma lipids. Additional studies are necessary to establish whether sodium-lithium countertransport is an independent predictor of risk of developing essential hypertension.