The impact of lifestyle-induced weight loss (WL) on appetite in patients with obesity remains controversial. This study aimed was to assess the short- and long-term impact of WL achieved by diet and exercise, on appetite in patients with obesity. Thirty-five (22 females) adults with severe obesity (BMI: 42.5{plus minus}5.0 kg/m2) underwent a 2-year WL program focusing on diet and exercise. Body weight (BW), cardiovascular fitness (VO2max), appetite feelings and plasma concentrations of insulin, active ghrelin (AG), glucagon-like peptide 1 (GLP-1), peptide YY (PYY) and cholecystokinin (CCK), in the fasting and postprandial states, were measured at baseline (B), week 4 (W4), 1 and 2-years (and average values for all fasting and postprandial time points computed). BW was significantly reduced and VO2max (ml/kg/min) increased at all time points compared with B (3.5, 8.1 and 8.4 % WL and 7, 11 and 8 % increase at W4, 1 and 2y, respectively). Basal hunger and average hunger and desire to eat were significantly increased at 1 and 2y. Basal fullness was significantly increased at W4 and average ratings reduced at 1y. Average AG and PYY were significantly increased, and insulin reduced, at all time points compared with B. Average GLP-1 was reduced at W4 and CCK increased at 2y. After lifestyle-induced WL, patients with severe obesity will, therefore, have to deal with increased hunger in the long-term. In conclusion, sustained WL at 2y achieved with diet and exercise is associated with increased hunger feelings and ghrelin concentration, but also increased postprandial concentrations of satiety hormones.