A genome-wide linkage scan was performed to identify genomic regions that influence levels of dehydroepiandrosterone (DHEA), DHEA sulfate (DHEAS), and DHEA fatty acid esters (DHEA-FA) at baseline and in response to 20 weeks of endurance exercise training in sedentary white and black participants in the HERITAGE Family Study. The baseline levels were log-transformed and adjusted for the effects of age and sex prior to genetic analysis. The training responses were adjusted for the effects of age, sex, and the baseline values. A total of 509 autosomal component polymorphic markers were used for the genome scan with an average spacing of 6.0 Mb. Multipoint variance components linkage analyses were performed in nuclear families containing 360 white and 106 black sibling pairs. We found 5 genomic regions with significant linkages for baseline DHEA-FA in whites, with log odd (LOD) scores over 3.6 (P < 2 × 10-5). They include (1) D1S468 (LOD 4.56, 2.533 Mb, 1p36.22); (2) D2S177 (LOD 5.65, 52.663 Mb, 2p16.3); (3) D4S2397 (LOD 3.98, 32.246 Mb, 4p15.2); (4) the paraoxonase loci (LOD 3.93∼3.99, 101.544∼102.933 Mb, 7q21.3), and D7S821 (LOD 3.88, 104.497 Mb, 7q22.1); and (5) D12S372 (LOD 4.66, 2.129 Mb, 12q13.33). In addition, we obtained evidence of suggestive linkages (2.2 < LOD < 3.6; 2 × 10-5 < P < 7 × 10-4) on chromosomes 3p, 6q, and 8q for baseline DHEAS; on chromosomes 2q, 3p, 9q, 10p, 16q, and 17p for baseline DHEA-FA in whites; and on chromosomes 9q and 11p for baseline DHEA in blacks. This is the first genome-wide linkage scan searching for genomic regions influencing human DHEA levels. Several potential candidate genes are located in these genomic regions, which warrant further studies in HERITAGE and other cohorts.