During the course of an investigation into the treatment of metabolic acidosis arising from total body perfusion, it was noticed that the intra-arterial administration of concentrated alkalies resulted in a fall in arteriovenous pressure difference at constant flow. A similar decline in peripheral resistance could be produced by hypertonic sugar and salt solutions. This response was found to be independent of the central nervous system. The role of the vasodilatation in the complex vasomotor reaction to the rapid intravenous injection of hyperosmotic agents was then investigated in the intact and vagotomized dog. It was found that when concentrations of up to 1,500 mOsm./L. were used, the predominant response was a delayed hypotension consistent with peripheral vasodilatation. This reaction was complicated by preliminary pulmonary hypertension when solutions containing more than 2,000 mOsm./L. were administered. Twenty per cent NaCl produced such a severe initial phase that the animals frequently died from acute cor pulmonale. The site of obstruction to blood flow through the lungs was variable. Fifty percent glucose could incite pulmonary hypertension, but urea was anomalous in that it was never observed to produce pulmonary vascular effects. Studies in the isolated perfused lung indicated that, again with the exception of urea, all solutions with an osmolarity equal or greater than 5 per cent NaCl evoked pulmonary hypertension. The increase in pulmonary vascular resistance was transitory in spite of recirculation. No response could be elicited when red cells were absent from the perfusate even though, under these conditions, the lung was still sensitive to serotonin. Microscopic examination of the circulation through the brain, lung, mesentery and thigh of both cat and dog demonstrated that intravascular red-cell agglutination occurred after regional arterial injection of highly concentrated salt and sugar solutions. This alteration in the stability of the red-cell stream is considered to be responsible for the obstructive effects of hyperosmotic agents previously attributed to vasospasm.