BACKGROUND: The identification of genetic factors controlling stress-responsiveness should advance the understanding of susceptibility to psychiatric illness. METHODS: Rat strains, F344/NHsd and LEW/NHsd, which differ in measures of stress-responsiveness and behaviors modeling psychiatric disorders, were bred to generate F2 progeny that were used in a quantitative trait loci (QTL) analysis to identify genomic regions influencing late-afternoon corticosterone levels. RESULTS: Regions on chromosomes 4 and 10 previously identified as influencing autoimmune phenomena were the most significant QTL observed, reaching suggestive significance at the genome-wide level. Congenic animals targeting these regions with F344/NHsd deoxyribonucleic acid on a DA/Bkl genomic background demonstrated corticosterone levels approximating those of F344/NHsd rats and differing significantly from DA/Bkl rats. CONCLUSIONS: Specific genomic regions influence both corticosterone levels and stress-related disease susceptibility. These findings not only represent the first identification of QTL controlling corticosterone levels but also suggest a mechanism underlying genetic differences in stress-responsiveness.