The transcription factor FOXC2 has been implicated in resistance to diet-induced obesity and insulin resistance. To investigate the possible role for FOXC2 in obesity and related phenotypes, we performed two association studies for obesity using unrelated case-control materials by genotyping the FOXC2 C-512T polymorphism. In the first study (127 obese and 127 normal-weight nondiabetic subjects matched for age and sex), the C-allele showed association with obesity, odds ratio 1.74 (1.12 to 2.73; p < 0.01) for the C- vs. T-allele and 1.81 (1.04 to 3.25; p < 0.05) for the C/C and C/T vs. T/T genotype. BMI was higher in carriers of the C/C and C/T genotype in normal weight [adjusted p value (p(adj)) = 0.02] but not in obese subjects (p(adj) = 0.1). In the replication study (223 obese and 231 nonobese subjects), subjects with the C/C genotype exhibited an increased risk for obesity, odds ratio 2.01 (1.15 to 3.52; p = 0.01). Obese carriers of the C-allele had lower high-density lipoprotein-cholesterol [1.1 (0.9 to 1.3) vs. 1.2 (1.0 to 1.4) mM, p(adj) = 0.006] and increased triglyceride levels (1.95 [1.30 to 2.68] vs. 1.60 [1.10 to 2.40] mM, p(adj) = 0.02) compared with obese carriers of the T/T genotype. Our data suggest that FOXC2 is a weak but consistent candidate gene for obesity and dyslipidemia.