Numerous studies have reported the mean value for Na+-Li+ countertransport to be increased in red blood cells from patients with essential hypertension. Although concomitant variables including age, body size, national origin, geographic location, gender, and family history of hypertension may affect Na+-Li+ countertransport values, most case-control studies have failed to assess the contribution of these factors to the differences in Na+-Li+ countertransport between hypertensive and normotensive groups. The present study was undertaken to provide estimates of Na+-Li+ countertransport in hypertensive and normotensive subjects after taking into account these potentially confounding sources of variation. In 187 subjects undergoing medical evaluation at the Mayo Clinic, Rochester, MN, the combined effects of variation in age, height, and weight accounted for 20.6% of the interindividual variability in Na+-Li+ countertransport. After adjustment to remove variability due to these concomitants, differences in national origin, region of birth, and place of current residence made no additional contribution to variability in this trait. There was no significant difference in mean adjusted Na+-Li+ countertransport between men and women (0.41 +/- 0.17 vs 0.40 +/- 0.12 [SD] mmol Li efflux/L red blood cells/hr; n = 107). The mean value for adjusted Na+-Li+ countertransport was significantly greater (p less than or equal to 0.001) in subjects with essential hypertension (0.44 +/- 0.15 mmol/L red blood cell/hr; n = 104) compared with normotensive subjects (0.31 +/- 0.07 mmol/L red blood cells/hr; n = 39) or subjects with borderline blood pressure elevation (0.35 +/- 0.11 mmol/L red blood cells/hr; n = 21). Subjects with a family history of hypertension in at least one parent or full sibling had significantly higher (p less than 0.02) Na+-Li+ countertransport values (0.42 +/- 0.16 mmol/L red blood cells/hr; n = 111) than those with no family history of hypertension (0.37 +/- 0.13 mmol/L red blood cells/hr; n = 76). These results suggest that increased mean Na+-Li+ countertransport in hypertensive subjects in this sample cannot be attributed to confounding effects of variation in age, body size, gender, national origin, birthplace, or residence. Forty-eight percent of subjects with essential hypertension had adjusted Na+-Li+ countertransport values above the range observed in normotensive controls.