Background: Post-stroke depression is a common consequence of stroke and can negatively affect the rehabilitation process in patients. This work was undertaken to examine the incidence, demographic factors and clinical determinants of post-stroke depression in 3 months after ischemic stroke in mainland Chinese patients. Methods: One hundred and sixty-five patients with acute ischemic stroke were included in the present work. The Diagnostic and Statistical Manual of Mental Disorders (fourth edition) diagnosis of post-stroke depression was evaluated by the World Health Organization Composite International Diagnostic Interview during the follow-up exam at 3 months after the stroke. The demographic factors and clinical variables at the time of stroke onset and 14 days after stroke were also examined. Results: The 3 month cumulative incidence of post-stroke depression was 27.3% in this patient population. The univariate analysis suggests that the female gender, past history of depression, marital status and level of handicap at 14 days after stroke were factors associated with the development of post-stroke depression. In the multivariate model, female gender [p=0.0040; odds ratio (OR)=3.550; 95% confidence interval (CI): 1.499-8.408], past history of depression (p=0.0010; OR=5.225; 95% CI: 1.959-13.940) and level of handicap at 14 days after stroke (p=0.0066; OR=1.607; 95% CI: 1.141-2.262) were further confirmed as demographic and clinical factors that correlate with the development of post-stroke depression. Conclusion: The present work suggests that female gender, history of depression and level of handicap at 14 days after stroke are three independent determinants of post-stroke depression occurrence during the first 3 months after ischemic stroke in mainland Chinese patients.