Context: Factors underlying variable weight loss (WL) after Roux-en-Y gastric bypass (RYGB) are poorly understood. Objective: Our objective was to gain insight on the role of gastrointestinal hormones on poor WL maintenance (P-WLM) following RYGB. Design and Patients: First, glucagon-like peptide-1 (GLP-1), peptide YY (PYY), and ghrelin responses to a standardized mixed liquid meal (SMLM) were compared between subjects with good WL (G-WL, n = 32) or P-WLM (n = 22). Second, we evaluated food intake (FI) following blockade of gut hormonal secretion in G-WL (n = 23) or P-WLM (n = 19) subjects. Finally, the impact of dietary-induced WL on the hormonal response in subjects with P-WLM (n = 14) was assessed. Setting: This study was undertaken in a tertiary hospital. Main Outcome Measures: In studies 1 and 3, the outcomes measures were the areas under the curve of gut hormones following a SMLM; in study 2, FI following subcutaneous injection of saline or octreotide were evaluated. Results: P-WLM associated a blunted GLP-1 (P =.044) and PYY (P =.001) responses and lesser suppression of ghrelin (P =.032) following the SMLM challenge. On saline day, FI in the G-WL (393 +/- 143 kcal) group was less than in the P-WLM (519 +/- 143 Kcal; P =.014) group. Octreotide injection resulted in enlarged FI in both groups (G-WL: 579 +/- 248 kcal, P =.014; P-WLM: 798 +/- 284 Kcal, P =.036), but the difference in FI between groups remained (P <.001). In subjects with P-WLM, dietary-induced WL resulted in larger ghrelin suppression (P =.046), but no change in the GLP-1 or PYY responses. Conclusion: Our data show gastrointestinal hormones play a role in the control of FI following RYGB, but do not support that changes in GLP-1, PYY, or ghrelin play a major role as determinants of P-WLM after this type of surgery.