We aimed to investigate whether genetic variants in the leptin-melanocortin system involved in anorexigenic signaling influence personality dimensions and psychopathological symptoms in eating disorders (ED) patients. The population consisted of 309 ED patients [221 with anorexia nervosa (AN) and 88 with bulimia nervosa (BN)] and 396 healthy controls. Patients underwent psychometric assessment using the Eating Disorders Inventory Test-2 (EDI-2) and the Symptom Checklist 90 Revised (SCL-90R) questionnaires. Fourteen tag-SNPs in the LEP, POMC, and MC4R genes, were determined. Drive for thinness (DT) was significantly affected by genetic variability. After correction for multiple testing, regression models showed that AN patients carrying the LEP rs11761556 CC variant genotype scored higher in this scale than AA/CA carriers did [mean difference = 4.43 (2.18-6.68), p <
0.001], although the significance was restrained to the restrictive subtype [4.92 (2.00-7.83), p = 0.001]. BN patients with the LEP rs10954173 AA genotype displayed lower scores [-8.7 (-12.31--3.91)
p <
0.001]. Finally, gene-gene interaction analyses revealed two SNP pairs associated with body-mass index in AN patients (LEPrs3828942-POMCrs1009388, p <
0.001 and LEP rs11763517-POMCrs1009388, p = 0.002). Regarding DT scores, the POMCrs6545975-LEP11763517 SNP pair showed the strongest effect (p <
0.001) in AN. Genetic variants in the leptin-melanocortin system, may interact to influence personality dimensions in ED patients, which highlights the importance of considering genetic factors in the pathophysiology of these disorders.