The ratio of pulmonary to systemic vascular resistance (Rp/Rs) largely determines the amount of left-to-right shunting and pulmonary to systemic flow rat (Qp/Qs) in the presence of a large isolated ventricular septal defect. The possibility that pharmacologic reduction of systemic vascular resistance with alpha-adrenergic receptor blockade or beta-adrenergic receptor stimulation would increase the ratio Rp/Rs, and therefore reduce the ratio Qp/Qs, was studied in dogs in which ventricular septal defects had been surgically created. Administration of phentolamine and phenoxybenzamine caused a 42% reduction in Rs and no reduction in Rp. Qs was unchanged and Qp declined by 24% and the ratio Qp/Qs fell by 32%. Infusion of the beta-adrenergic receptor stimulant isoproterenol also reduced Qp/Qs. However, this was accomplished as a result of an increase in Qs and at the expense of an increase in heart rate. As a decline in the ratio Qp/Qs has been shown to be beneficial to patients with large left-to-right shunts, pharmacologic reduction of systemic vascular resistance may prove to be helpful in treating congestive heart failure in those patients with large left-to-right shunts at the ventricular level who are refractory to the usual decongestive measures.