The prevalence of morbid obesity and its associated metabolic complications has risen rapidly in the past decade. Recently, we have established the transcriptome of the visceral adipose tissue of nondiabetic severely obese men with and without metabolic syndrome (MetS) that provided new candidate genes for cardiovascular disease (CVD) risk factors. The oxysterol-binding protein–like protein 11 (OSBPL11) that belongs to the OSBP family of intracellular receptors was one of the genes found to be significantly overexpressed in the MetS group. To determine whether OSBPL11 gene polymorphisms are associated with CVD risk factors and diabetes, OSBPL11 gene promoter and coding regions were sequenced in 25 individuals and six tagging single-nucleotide polymorphisms (SNPs) capturing 85% of gene sequence–derived common genetic variability (minor allele frequency (MAF) > 5%) were genotyped in two samples for a total of 962 obese individuals. Using a multistage experimental design, χ2-tests and logistic regressions were applied to compare genotype frequencies and to compute odds ratios (ORs) for low and high CVD risk groups. Significant associations between rs1055419 and diastolic blood pressure (OR = 0.53; P = 0.01) were found whereas IVS12+95 T>C, a newly discovered SNP, was associated with low-density lipoprotein–cholesterol levels (OR = 1.63; P < 0.001), hyperglycemia/diabetes (OR = 1.48; P < 0.004) as well as with MetS per se (OR = 1.56; P < 0.01). These results suggest that the OSBPL11 gene is involved in cholesterol and glucose metabolism in obese individuals.