This study examined gastrointestinal hormone and peptide responses when glucose was ingested after prolonged exercise. Six endurance-trained male athletes ran on a treadmill for 2 hours at 60% VO_2max. Immediately after the run the athletes consumed 75 g of glucose in 250 ml of water (ExGLU), or flavored water as a placebo control (ExPL). On a separate visit the athletes rested for 2 hours and then consumed glucose (ConGLU). During the first 60 min of recovery from exercise alone (ExPL), plasma vasoactive intestinal peptide (VIP), gastrin and glucagon-like peptide-1 (GLP-1) all increased significantly, while glucose, insulin and gastric inhibitory polypeptide (GIP) were unchanged from the immediate postexercise value. When glucose was ingested after exercise (ExGLU), glucose, insulin, VIP, gastrin, GLP-1, and GIP were all increased (P<0.01). However, when glucose was ingested after resting for two hours (ConGLU) VIP levels were unaffected, while glucose, insulin, gastrin, GLP-1, and GIP levels increased (P<0.05). The plasma glucose response was greater (P<0.03) and the plasma insulin response was lower (P<0.004) during ExGLU compared to ConGLU. There was a significantly higher (P<0.01) VIP response during the initial period of recovery in ExGLU compared to both ExPL and ConGLU. Plasma VIP showed a modest negative correlation with circulating glucose (r=-0.35, P<0.03) and insulin (r=-0.37, P<0.03) during the ExGLU recovery period. In summary, when glucose is ingested after prolonged exercise, there is mild insulin resistance and a corresponding rapid transitory increase in plasma VIP. These data suggest that VIP may play an important glucoregulatory role when glucose is ingested during the immediate postexercise recovery period.