The neuropeptide Y2 receptor (NPY2R) has been implicated in body weight regulation both in humans and rodents. We investigated if genetic variation in the NPY2R gene is associated with obesity in German extremely obese children and adolescents. The coding sequence and predicted promoter of the NPY2R were screened for variations. Subsequently, case-control (184 extremely obese children and adolescents: mean body mass index [BMI] 35.7+/-6.1 kg/m(2), 277 lean students: mean BMI 18.2+/-1.1 kg/m(2)) and family-based (770 parental pairs with a total of 1081 obese off-spring) association analyses were conducted in independent samples. We identified 14 sequence variants (seven novel variants including two coding variants c.369C >T and c.834G >A), five of which were detected once, each in the heterozygous state. In case-control analyses we did not detect association with obesity for seven common (minor allele frequency >1%) variants (all p >0.16); additional gender-stratified analyses employing several genetic models and haplotype analyses were also nonsignificant. Furthermore, in a family-based association study for coding synonymous SNP rs1047214 (Ile195) we found no evidence for a transmission disequilibrium in the total or in the gender-stratified PDT analyses (all p >0.50). In conclusion, we did not find evidence for an involvement of genetic variation in the NPY2R in early onset obesity in German samples.