Weight gain is a frequent adverse effect of many second-generation antipsychotic (SGA) drugs. Although a number of candidate gene studies have focused on SGA-related weight gain, a clinical benefit for pharmacotherapy has not been achieved as yet. Genome-wide association studies offer great potential of identifying novel candidate genes and help to complete the search for relevant polygenetic risk factors. A polymorphism near the human melanocortin 4 receptor gene (MC4R) was associated with overweight and body mass index in recent studies. Owing to the central role of the MC4R receptor in energy homeostasis, we investigated the influence of the rs17782313 polymorphism on SGA-related weight gain. Three hundred forty-five white inpatients receiving different atypical antipsychotics (clozapine, olanzapine, risperidone, paliperidone, quetiapine, or amisulpride) were included in a naturalistic design. After 4 weeks of treatment, patients homozygous for the rs17782313 C-allele had a significantly higher risk of weight gain and body mass index increase, with a dose effect of the C-allele. In a subpopulation without additional weight gain-inducing comedication, the 106 TT-allele carriers gained on average 1.09% of their baseline weight within the 4 weeks of treatment, whereas the 57 CT-allele carriers and the 9 CC-allele carriers gained 3.28% and 5.47% (P = 0.003). Our findings indicate that the rs17782313 polymorphism could increase the amount of SGA-related weight gain and may influence MC4R expression, which could result in an imbalance of energy homeostasis. Nevertheless, further studies are needed to elucidate the role and mechanism of this polymorphism.