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Low vitamin D is linked to major depressive disorder (MDD) through affecting the brain. Gender difference is apparent in MDD and vitamin D level. We aimed to examine the association between gender, vitamin D, clinical presentations, and brain functional connectivity in a large cohort of MDD patients and comparison subjects. Resting-state functional MRI data from 122 patients and 119 controls were collected to perform a combined analysis of functional connectivity density (FCD) and seed-based functional connectivity (FC). Peripheral venous blood samples were obtained to measure serum concentration of vitamin D (SCVD). Clinical presentations (symptoms profiles and cognition) were also assessed. We found an interaction of group and gender on SCVD in which MDD patients demonstrated lower SCVD than controls in females rather than males. Concurrently, lower SCVD was associated with worse cognitive performance (prospective memory and sustained attention). Compared with controls, female MDD patients showed reduced FCD and FC of the left middle frontal gyrus, which were related to lower SCVD. Importantly, these FCD and FC changes mediated the relationship between lower SCVD and cognitive dysfunction. Our findings suggest that functional connectivity abnormalities may serve as neural substrates underlying the associations between low vitamin D and cognitive impairments in female MDD patients, providing unique insight into treatment and prevention of MDD and its related cognitive dysfunction from the perspective of regulating circulating vitamin D. • Depressive patients exhibited lower vitamin D than controls in females but not males. • There is a female-specific relation between lower vitamin D and poorer cognition. • Depression-related functional connectivity changes related with vitamin D in females. • Connectivity changes mediated relations between vitamin D and cognition in females. [ABSTRACT FROM AUTHOR]