OBJECTIVE Epidemiological studies suggest that smoking increases the risk of type 2 diabetes. We hypothesized that smoking-derived nicotine and ensuing activation of nicotinic cholinergic receptors in the gastrointestinal tract and the autonomic nervous system would have a detrimental effect on postprandial glucose metabolism and, thus, potentially constitute a link between smoking and the development of type 2 diabetes. RESEARCH DESIGN AND METHODS Wesubjected11maleheavy smokers totwoidentical4-hliquidmixed-meal tests:one with concomitant cigarette smoking (immediately before and aftermeal intake) and one without smoking. Twelve age-, sex-, and BMI-matched nonsmokers underwent an identical meal test without smoking. RESULTS The smokers were characterized by higher fasting plasmaconcentrations of glucagon compared with the nonsmokers.Among smokers, cigarette smoking before and after themeal significantly reducedpostprandialplasmaglucose excursions. Therewereno differences in gut or pancreatic hormone concentrations between the test days in the smoking group, and the responses were similar to those in the control group. CONCLUSIONS Our results suggest that smoking in association with meal intake decreases the postprandial plasma glucose concentrations, possibly through decreased gastric emptying, and that elevated fasting glucagon concentrations rather than smokinginduced alterations in postprandial glucose and hormone responsesmay be associated with the elevated risk of type 2 diabetes in chronic smokers.