In fasted man, ethanol lowers plasma glucose by inhibiting gluconeogenesis with concomitant suppression of insulin release. Since glucose regulation of glucagon (IRG) secretion may be insulin dependent, we have evaluated IRG secretion in this setting of hypoglycemia and insulin deficiency. Mean IRG levels in six men fasted for fifty-six hours rose gradually from a basal level of 57 pg/ml. to 101 pg/ml. During the subsequent four-hour ethanol infusion, mean glucose concentration fell only 18 mg. per 100 ml. (26 per cent of pre-infusion values) yet IRG tripled to 265 pg/ml. Insulin (IRI) fell to unmeasurably low values. Alcohol given after only eight hours of fasting has no effect on plasma levels of glucose, IRG and IRI. These results suggest that the small decrease in extracellular glucose combined with relative insulin deficiency may cause inordinate intra-alpha cell glucopenia and result in exaggerated glucagon release.