Xuan-qiang Tu,1,* Ze-hua Lai,1,* Yu Zhang,2 Kai-qi Ding,1 Fei-yue Ma,3 Guo-Yuan Yang,1 Ji-rong He,3 Li-li Zeng1 1Department of Neurology and Institute of Neurology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, People’s Republic of China; 2Department of Neurology and Institute of Neurology, Ruijin Hospital North, School of Medicine, Shanghai Jiao Tong University, Shanghai, People’s Republic of China; 3Department of Neurology and Institute of Neurology, Ruijin Hospital Luwan Branch, Shanghai Jiaotong University School of Medicine, Shanghai, People’s Republic of China*These authors contributed equally to this workCorrespondence: Li-li Zeng No. 197 Ruijin Second Road, Huangpu District, Shanghai, 200025, People’s Republic of ChinaTel +86-13816290607Email llzeng@126.comJi-rong He No. 149 Chongqing South Road, Huangpu District, Shanghai, People’s Republic of ChinaTel +86-13162762045Email kyo3shao@aliyun.comObjective: This study aimed to explore the correlation between white matter hyperintensity (WMH) and post-stroke depression (PSD) at 3 months, and to further investigate sex differences in the pathogenesis of PSD.Methods: A total of 238 consecutive patients with acute cerebral infarction were recruited. PSD was assessed at 2 weeks and at 3 months after stroke onset. All stroke cases were divided into four subgroups according to the diagnosis of depression at two time nodes: continuous depression; depression remission; late-onset PSD; and continuous non-depression. The Fazekas and Scheltens visual rating scales were adopted to assess WMH.Results: Logistic regression revealed that the presence of periventricular white matter hyperintensity (PVWMH) at baseline in male patients was an independent risk factor for PSD at 3 months. Further subgroup analysis revealed that PVWMH was associated with late-onset PSD in males, but not with continuous depression 3 months after stroke. Male acute stroke patients with PVWMH at baseline were more likely to develop PSD at 3 months, especially late-onset PSD.Conclusion: Our data suggest that sex differences may influence the pathogenesis of PSD.Keywords: sex difference, acute cerebral infarction, leukoencephalopathy, affective disorder, post-stroke depression