<p>Chronic psychosocial stress is heterogeneously related to serum cholesterol and glucocorticoids in epidemiologic studies. Moreover, we have found that adiponectin receptor 2 (AdipoR2) signaling pathway plays a role in mediating the effect of glucocorticoids on hepatic cholesterol metabolism. The present study aims to further investigate the role of AdipoR2 in the relationship between glucocorticoid and serum cholesterol under experiencing a same catastrophic earthquake as a stress in students. A total of 722 students who experienced the same earthquake were included in this study. Serum levels of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C) were measured by routine methods, and serum cortisol by enzyme-linked immunosorbent assays. Genotyping of <i>AdipoR2</i> rs12342 was performed by polymerase chain reaction-restriction fragment length polymorphism analyses and verified by DNA sequencing. Here we show that not all individuals exhibit an increase in serum cortisol in response to stress. Furthermore, female subjects displayed higher levels of both serum cortisol and cholesterol compared to males following exposure to stress. The genotype of <i>AdipoR2</i> rs12342 was found to be associated with serum TC and LDL-C levels only in male subjects under increased cortisol. Meanwhile, cortisol was associated with TC in all GG homozygotes, while its association with serum LDL-C was specific to male GG homozygotes only. These results indicate that the impact of stress on serum cholesterol levels is mediated by serum cortisol and <i>AdipoR2</i> rs12342 in a gender-specific manner, which may provide novel insights into the heterogeneous relationship between stress and serum cholesterol.</p>