The exclusion of the proximal small intestine is thought to play a major role in the rapid improvement in the metabolic control of diabetes after gastric bypass. In this randomized, prospective, parallel group study, we sought to evaluate and compare the effects of laparoscopic Roux-en-Y gastric bypass (LRYGB) with those of laparoscopic sleeve gastrectomy (LSG) on fasting, and meal-stimulated insulin, glucose, and glucagon-like peptide-1 (GLP-1) levels. Thirteen patients were randomized to LRYGB and 14 patients to LSG. The mostly nondiabetic patients were evaluated before, and 1 week and 3 months after surgery. A standard test meal was given after an overnight fast, and blood samples were collected before and after food intake in both groups for insulin, GLP-1, glucose, PYY, and ghrelin concentrations. This trial was registered in www.clinicaltrials.gov (NCT00356213) before the first patient was randomized. Body weight and body mass index decreased markedly (P < 0.002) and comparably after either procedure. Excess BMI loss was similar at 3 months (43.3 +/- 12.1% vs. 39.4 +/- 9.4%, P > 0.36). After surgery, patients had markedly increased postprandial plasma insulin and GLP-1 levels, respectively (P < 0.01) after both of these surgical procedures, which favor improved glucose homeostasis. Compared with LSG, LRYGB patients had early and augmented insulin responses as early as 1-week postoperative; potentially mediating improved early glycemic control. After 3 months, no significant difference was observed with respect to insulin and GLP-1 secretion between the 2 procedures. Both procedures markedly improved glucose homeostasis: insulin, GLP-1, and PYY levels increased similarly after either procedure. Our results do not support the idea that the proximal small intestine mediates the improvement in glucose homeostasis.