To explore the mechanism by which elevated sodium-lithium countertransport activity (SLC) associates with both predisposition to hypertension and diabetic nephropathy, we investigated the interrelationships among SLC, intracellular sodium concentration ([Na]i), intracellular free calcium-ion concentration ([Ca2+]i), diabetic nephropathy, hypertension, family history of hypertension, and other factors in 48 patients with Type 2 diabetes and 24 healthy controls. There was a significant correlation between SLC and [Na]i (r = 0.36, p < 0.05), [Na]i and [Ca2+]i (r = 0.47, p < 0.01), SLC and [Ca2+]i (r = 0.46, p < 0.01), and between HbA1c and [Ca2+]i (r = 0.38, p < 0.01). Both [Na]i and [Ca2+]i were significantly higher in the patients with elevated SLC than in those with normal SLC (p < 0.01 and p < 0.05, respectively). In stepwise multivariate regresssion analysis, [Na]i, HbA1c, and SLC appeared as independent determinants of [Ca2+]i. These data suggest a significant correlation of elevated SLC with increased [Na]i and [Ca2+]i. This may be a possible mechanism underlying the close association of elevated SLC with both predisposition to hypertension and diabetic nephropathy.