The known genetic variants determining plasma HDL cholesterol (HDL-C) levels explain only part of its variation. Three hundred eighty-four single nucleotide polymorphisms (SNPs) across 251 genes based on pathways potentially relevant to HDL-C metabolism were selected and genotyped in 3,575 subjects from the Doetinchem cohort, which was examined thrice over 11 years. Three hundred fifty-three SNPs in 239 genes passed the quality-control criteria. Seven SNPs [rs1800777 and rs5882 in cholesteryl ester transfer protein (CETP); rs3208305, rs328, and rs268 in LPL; rs1800588 in LIPC; rs2229741 in NRIP1] were associated with plasma HDL-C levels with false discovery rate (FDR) adjusted q values (FDR_q) , 0.05. Five other SNPs (rs17585739 in SC4MOL, rs11066322 in PTPN11, rs4961 in ADD1, rs6060717 near SCAND1, and rs3213451 in MBTPS2 in women) were associated with plasma HDL-C levels with FDR_q between 0.05 and 0.2. Two less well replicated associations (rs3135506 in APOA5 and rs1800961 in HNF4A) known from the literature were also observed, but their significance disappeared after adjustment for multiple testing (P 5 0.008, FDR_q 5 0.221 for rs3135506; P 5 0.018, FDR_q 5 0.338 for rs1800961, respectively). In addition to replication of previous results for candidate genes (CETP, LPL, LIPC, HNF4A, and APOA5), we found interesting new candidate SNPs (rs2229741 in NRIP1, rs3213451 in MBTPS2, rs17585739 in SC4MOL, rs11066322 in PTPN11, rs4961 in ADD1, and rs6060717 near SCAND1) for plasma HDL-C levels that should be evaluated further. Numerous clinical and epidemiological studies have demonstrated an inverse and independent association between plasma concentrations of HDL cholesterol (HDL-C) and the risk of coronary heart disease (1). The most popular mechanistic explanation has been that HDL functions in reverse cholesterol transport, removing cholesterol from peripheral tissues and delivering it to the liver for biliary excretion and to steroidogenic organs for steroid hormones synthesis (2). Although efflux of cholesterol from macrophages represents only a tiny fraction of overall cellular cholesterol efflux, it is in fact, the most important with regard to antiatherogenic effects (3). More recently, a variety of other functions of HDL have been described, primarily based on in vitro assays, including anti-inflammatory, antioxidant, antithrombotic, and nitric oxide-inducing mechanisms that could also contribute to its antiatherogenic effects (4, 5).Current evidence suggests that blood lipids are complex phenotypes, influenced by environmental and genetic factors. It has been well established that body weight (6), current smoking habits (7), exercise (8), alcohol use (9), and dietary fat intake (10) influence plasma HDL-C levels. Several twin and family studies indicate that heritability estimates for blood levels of HDL-C range from 24% to 83%, with most studies in the 40% to 60% range (11). Mutations in genes including ABC transporter A1 (ABCA1), apolipoprotein A1, and lecithin cholesterol transferase (LCAT) are ...