The effects of the calcium antagonist diltiazem on diastolic blood pressure and various parameters of erythrocyte membrane cation transport were evaluated in hypertensive patients with diastolic blood pressure between 95 and 110 mm Hg in a placebo-controlled, double-blind parallel study. Twenty-one patients completed the study; 13 received placebo, while 8 received diltiazem. Diastolic blood pressure, intracellular sodium and calcium concentrations, ouabain-sensitive Na+, K+-adenosine triphosphatase (ATPase) activity, and net sodium efflux and potassium influx across red blood cell membranes were examined in both groups at the end of placebo run-in, at the end of the titration phase, and at the completion of study. In the placebo group, none of the parameters changed significantly. In the drug-treated group, diastolic blood pressure declined by approximately 10% (placebo, 95.1 ± 8.9; drug-treated, 86.9 ± 4.9 mm Hg;p< 0.03) at the end of the study. There were also reductions in intracellular sodium (placebo, 7.9 ± 1.8; drug-treated, 5.2 ± 0.4 mmol/L cells;p< 0.002) and calcium (placebo, 13.5 ± 1.6; drug-treated 10.8 ± 3.3 Mmol/L cells;p< 0.03) concentrations, accompanied by a simultaneous rise in the activity of the ouabain-sensitive Na+, K+-ATPase of erythrocyte membranes (placebo, 7.1 ± 1.1 × 10-J; drug-treated, 9.0 ± 0.6 × 10–2 fiM inorganic pbosphate/hr/mg;p< 0.001) at the end of the study. However, no significant change in the ouabaininsensitive moiety of the ATPase pump was found. Diltiazem treatment increased net sodium efflux and potassium influx. It is concluded that diltiazem reduces diastolic blood pressure of hypertensive subjects. Erythrocyte studies indicate that diltiazem not only blocks entrance of calcium into the cells but may also stimulate Na+, K+-ATPase activity, resulting in reduction in intracellular sodium concentration, thus suggesting a possible dual mechanism for its antihypertensive effects.