Objective: Appetite responses to 3 days of overfeeding (OF) were examined as correlates of longitudinal weight change in adults classified as obesity prone (OP) or obesity resistant (OR). Methods: OP (n = 22) and OR (n = 30) adults consumed a controlled eucaloric and OF diet (140% of energy needs) for 3 days, followed by 3 days of ad libitum feeding. Hunger and satiety were evaluated by visual analog scales. Ghrelin and peptide YY (PYY) levels were measured during a 24-hour inpatient visit on day 3. Body weight and composition were measured annually for 4.0 ± 1.3 years. Results: Dietary restraint and disinhibition were greater in OP than OR (mean difference: 3.5 ± 1.2 and 3.3 ± 0.9, respectively; P < 0.01) participants, and disinhibition was associated with longitudinal weight change (n = 48; r = 0.35; P = 0.02). Compared with the eucaloric diet, energy intake fell significantly in OR participants following OF (P = 0.03) but not in OP (P = 0.33) participants. Twenty-four-hour PYY area under the curve values increased with OF in OR (P = 0.02) but not in OP (P = 0.17) participants. Furthermore, changes in PYY levels with OF correlated with measured energy intake (r = -0.36; P = 0.01). Conclusions: Baseline disinhibition and PYY responses to OF differed between OP and OR adults. Dietary disinhibition was associated with 5-year longitudinal weight gain. Differences in appetite regulation may underlie differences in propensity for weight gain.