The purpose of the present work was to study the effect of a methionine-enkephalin analogue (FK 33-824) on glucose tolerance in man. Groups of 5 to 8 normal subjects were given a 0.5 mg im injection of the drug or placebo just before a 100 g oral glucose load or a 0.5 g/kg iv glucose load. In the enkephalin analogue treated subjects, diminished insulin response to glucose was observed following the oral glucose load, with insulin values significantly lower than in the controls from time 10 to 90 min, but no corresponding change in the glucose curve. This effect was not observed when glucose was given iv in another group of 5 subjects in whom the significant blunting of the insulin response was accompanied by a significant decrease in glucose tolerance. These observations demonstrate that in man, enkephalin produces a decrease in insulin secretion in response to both oral and iv glucose loads. The absence of any marked impairment in glucose tolerance in the oral test in spite of the decreased insulin response suggests that enkephalin might have an additional effect in delaying glucose absorption.