Growth hormone release inhibiting hormone (GHRIH) was administered by constant infusion over 75 minutes to eight acromegalic patients at different doses. 100 to 1,000 μg were equally effective in reducing circulating growth hormone (GH) levels; 25 μg lowered GH levels in only five patients, and at this dose the extent of the fall was smaller than from doses of 100 μg or more. 10 μg was ineffective. Injection of single doses of 500 μg by intravenous, subcutaneous, and intramuscular routes caused only small and transient reductions in GH levels, though the effect was improved by injecting the hormone intramuscularly in 2 ml of 16% gelatin. Injection of a suspension of 4 mg GHRIH in 1 ml of arachis oil lowered growth hormone levels for between three and four hours. In four acromegalic patients an oral 50-g glucose tolerance test was performed during a continuous infusion of either saline or 1,000 μg GHRIH. The “paradoxical” rise in growth hormone seen in these patients during the saline infusion was suppressed by GHRIH. The blood glucose responses were, moreover, modified by GHRIH in that the peak was delayed and occurred at the end of the infusion in each case. A “normal” glucose tolerance curve was converted to a “diabetic” type of response in two patients. This effect could be accounted for by the inhibition of insulin secretion known to occur with large doses of GHRIH. We speculate that acromegaly may be primarily a hypothalmic disease due to deficiency of GHRIH resulting in excessive secretion of growth hormone from the pituitary and adenoma formation due to inappropriate and prolonged stimulation of the pituitary.