Background <p>Available evidence indicates that blood-brain-barrier (BBB) dysfunction exacerbates with the advancing age and is implicated in a variety of neurological diseases and that there are significant sex differences in these diseases. However, the sex differences and age-related changes in BBB structure and function are still unclear under physiological conditions.</p> Methods <p>In this study, the mRNA was extracted from the cortical tissues and brain microvessels of male and female mice aged 3 months and 10 months to detect the expression of important BBB-related genes by qPCR.</p> Results <p>Under physiological conditions, compared with age-matched male counterparts, female mice reported a significantly lower mRNA expression of tight junction-related genes (cldn5 and occludin), transporters (Glut1 and D-gp), pericyte marker (Pdgfrb), microvessel marker (Cd31), basement membrane component (Col4a2), glycocalyx-related genes (Hs3st1, Extl2, and Clgalt), vascular homeostasis-related genes (Hif1a, Ddit4, and Pik3ca), and some regulatory genes (Adm, Zfpm2 and Nr3c1). A similar outcome was found in the 10-month mice when compared with the 3-month counterparts.</p> Conclusion <p>This study systematically analyzes the expression characteristics of key BBB regulatory genes in different sexes and ages under physiological conditions and reveals a marked sex difference in the expression of BBB structure/function-related genes, which may persist with the advancing age. The findings may provide important theoretical insights into the pathogenesis of sex-and age-related neurological diseases.</p>