The intravenous administration of griseofulvin in doses of 3.0 mg/kg to 32 anesthetized open-chest dogs produced marked increments (43%) in isometric systolic force measured by a strain gauge. These changes were accompanied by an increase (22%) in heart rate and a decrease (25%) in blood pressure. The effect was unaltered by clamping the blood supply to and from the adrenal glands or by previous treatment with 1 mg/kg reserpine, 0.4 mg/kg propranolol HCl, 10 mg/kg hexamethonium chloride, 1 mg/kg phentolamine HCl or 2 mg/kg atropine. In 11 anesthetized open-chest rats and 7 isolated rabbit hearts, griseofulvin also increased the force of contraction. It may be inferred from these experiments that griseofulvin has a direct action on the cardiovascular system rather than one mediated through neurogenic or hormonal mechanisms. These cardiovascular changes may occur in patients in whom griseofulvin is used in the treatment of fungus diseases.