Objective: To examine the effect of an equivalent weight loss, by gastric bypass surgery (GBP) or by diet, on peptide YY3-36 (PYY3-36), ghrelin, and leptin levels and to determine the effect of diabetes status on PYY3-36 levels. SUMMARY BACKGROUND DATA:: The increased PYY3-36 levels after GBP may be involved in the magnitude and the sustainability of weight loss after surgery. METHODS:: Of the 30 morbidly obese women who participated in the study, 21 had type 2 diabetes mellitus, and were studied before and after equivalent weight loss of 10 kg by either GBP (n = 11) or by diet (n = 10). RESULTS:: PYY3-36 levels were higher in obese diabetic as compared with nondiabetic individuals (64.1 ± 34.4 pg/mL vs. 39.9 ± 21.1 pg/mL; P < 0.05). PYY3-36 levels increased markedly in response to oral glucose after GBP (peak: 72.3 ± 20.5 pg/mL-132.7 ± 49.7 pg/mL; P < 0.001; AUC0-180: 51.5 ± 23.3 pg/mL.min-91.1 ± 32.2 pg/mL.min P < 0.001), but not after diet (peak: 85.5 ± 51.9 pg/mL-84.8 ± 41.13 pg/mL; P = NS; AUC0-180: 68.3 ± 38.5 pg/mL.min-61.1 ± 42.2 pg/mL.min P = NS). Fasting ghrelin levels increased after diet (425 ± 91 pg/mL-519 ± 105 pg/mL; P < 0.05), but did not change after GBP (506 ± 121 pg/mL-482 ± 196 pg/mL; P = NS). CONCLUSIONS:: Diabetes status seems to be a determinant of PYY3-36 levels. GBP, but not diet-induced weight loss, resulted in markedly increased glucose-stimulated PYY3-36 levels. The increase in stimulated PYY3-36 levels after GBP is likely a result of the surgery rather than a secondary outcome of weight loss. Changes in PYY3-36 levels and ghrelin could contribute to the success of GBP in sustaining weight loss.