Context: Appetite-related hormones may play an important role in weight regain after obesity therapy.Objective: Our objective was to investigate the potential involvement of ghrelin, leptin, and insulin plasma levels in weight regain after a therapeutic hypocaloric diet.Design: A group of obese/overweight volunteers (49 women and 55 men; 35 ± 7 yr; 30.7 ± 2.4 kg/m2) followed an 8-wk hypocaloric diet (−30% energy expenditure) and were evaluated again 32 wk after treatment. Body weight as well as plasma fasting ghrelin, leptin, and insulin concentrations were measured at three points (wk 0, 8, and 32).Results: After the 8-wk hypocaloric diet, the average weight loss was −5.0 ± 2.2% (P < 0.001). Plasma leptin and insulin concentrations decreased significantly, whereas ghrelin levels did not markedly change. In the group regaining more than 10% of the weight loss, leptin levels were higher (P < 0.01), whereas ghrelin levels were lower (P < 0.05). No differences were observed in insulin levels. Weight regain at wk 32 was negatively correlated with ghrelin and positively associated with leptin levels at baseline (wk 0) and endpoint (wk 8). These outcomes showed a gender-specific influence, being statistically significant among men for ghrelin and between women for leptin. Moreover, a decrease in ghrelin after an 8-wk hypocaloric diet was related to an increased risk for weight regain (odds ratio = 3.109; P = 0.008) whereas a greater reduction in leptin (odds ratio = 0.141; P = 0.001) was related to weight-loss maintenance.Conclusions: Subjects with higher plasma leptin and lower ghrelin levels at baseline could be more prone to regain lost weight, and hormones levels could be proposed as biomarkers for predicting obesity-treatment outcomes.