Adrenomedullin (ADM) is a vasoactive peptide found to be related to obesity and its comorbidities: type 2 diabetes, hypertension, atherosclerosis, and coronary heart disease. ADM is increased both in plasma and in adipose tissue of obese individuals when compared to lean subjects and is considered as a member of the adipokine family. We determined plasma midregional proadrenomedullin (MR-proADM) concentrations in a cohort of 357 subjects with BMI ranging from 17.5 to 42.3 kg/m2 and no additional medical history. In parallel, 28 severely obese patients scheduled to undergo laparoscopic Roux-en-Y gastric bypass (RYGB) surgery were studied at two time points: before and 1 year after surgery. Outcome measurements were: MR-proADM, cortisol, leptin, C-reactive protein (CRP) thyroid-stimulating hormone (TSH), creatinine and metabolic parameters. BMI correlated significantly to plasma MR-proADM levels (r=0.714, P<0.001), also after adjustment for age and gender (r=0.767, P<0.001). In obese subjects, there was a positive relationship between MR-proADM and leptin (r=0.511, P=0.006). Following RYGB, plasma MR-proADM decreased from 0.76+/-0.03 to 0.62+/-0.02 pg/ml (P<0.0001). RYGB-induced changes in MR-proADM correlated significantly to changes in leptin (r=0.533, P=0.004) and in CRP (r=0.429, P=0.023). We conclude that BMI is an independent predictor of circulating MR-proADM levels. Weight loss after RYGB is associated with a significant decrease in plasma MR-proADM, which is related to surgery-induced changes in both circulating leptin and systemic inflammation.