Bariatric surgery remains the most effective treatment option for obesity, and gut hormones are implicated in the reduction of appetite and weight after Roux-en-Y gastric bypass. Compared with lean and obese controls, patients following gastric bypass had increased postprandial plasma Peptide YY (PYY) and glucagon-like peptide 1 (GLP-1) favouring enhanced satiety. None of these effects were observed in patients losing equivalent weight through gastric banding. PYY and GLP-1 changes correlate within the first week after gastric bypass with changes in appetite. Postprandial PYY and GLP-1 profiles start rising as early as 2 days after gastric bypass. In patients with poor weight loss after gastric bypass associated with increased appetite, the postprandial PYY and GLP-1 responses are attenuated compared with patients with good weight loss. Moreover, using a rodent model of bypass, we showed elevated PYY and GLP-1 in bypassed rats compared with sham-operated rats. Blockade of endogenous PYY with antibodies increased food intake in bypassed rats prepared under anaesthesia. Inhibiting gut hormone responses, including PYY and GLP-1 after gastric bypass in humans, results in return of appetite and increased food intake. In conclusion the attenuated appetite after gastric bypass is associated with elevated PYY and GLP-1 concentrations, and appetite returns when the release of gut hormones is inhibited. The results suggest a role for gut hormones in the mechanism of weight loss after gastric bypass and may have implications for the treatment of obesity.