Sodium-lithium countertransport activity in red blood cells relates to blood pressure (BP) and the prevalence of hypertension. This study investigated in adults the relation of sodium-lithium (Na-Li) countertransport to BP change from baseline to 6-year follow-up. In the Gubbio Population Study, 4210 men and women were 18 to 74 years old at baseline (1983-1986), and 3766 had a valid baseline Na-Li countertransport measurement; of these, 2729 were reexamined at 6 years of follow-up (1989-1992) and made up the study cohort. At baseline, data collection included age, height, weight, BP, pulse rate, drug treatment, alcohol intake, ratio of sodium to potassium in spot urine, plasma cholesterol, and Na-Li countertransport in red blood cells. At 6-year follow-up, data for age, BP, and drug treatment were collected as at baseline. From baseline, average BP declined for people on antihypertensive medication at follow-up and for those with baseline BP greater than or equal to 140/90 mm Hg (systolic/diastolic) and did not change or increased for the remaining participants. In quartile and correlation analyses controlled for sex, baseline BP, and antihypertensive treatment, BP change related significantly and directly to baseline Na-Li countertransport. In multiple linear regression analyses done for the entire cohort with control for other confounders, the regression coefficient of baseline Na-Li countertransport to BP change over time was positive and borderline significant. The Na-Li countertransport coefficient was positive and significant when analyses were done with the use of a categorical value of baseline Na-Li countertransport (quartile 4 and quartiles 1 through 3 combined). In both models, the Na-Li countertransport coefficient was the strongest for people with baseline BP greater than or equal to 120/80 mm Hg or for people with baseline age of 45 years or older. In conclusion, Na-Li countertransport significantly relates to BP change over time in adults.