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The pharmacodynamics and pharmacokinetics of isosorbide, a recently developed, well‐tolerated, orally effective osmotic diuretic, were evaluated. Normal male volunteers received 0.25 to 1.5 Gm. per kilogram of isosorbide and 50 mg. of hydrochlorothiazide, alone and in combination with isosorbide. Dose response effects of isosorbide on water and osmolar excretion were statistically significant. The diuretic effect of isosorbide and hydrochlorothiazide was synergistic. The absorption, distribution, and fate of 14C isosorbide were studied before and after loading with unlabeled drug. Orally administered isosorbide appeared rapidly in the plasma and was excreted unchanged in the urine with a mean disappearance half‐time of 8 hours. There were no significant side effects.