Background: Several studies have described the frequency and risk factors of post-stroke depressive symptoms (PSDS). However, most studies did not exclude patients with depressive symptoms shortly before stroke and paid little attention to prestroke risk factors of depression, including previous depressive episodes, white matter lesions, and brain atrophy. These are potential limitations to assess the true effect of stroke on the occurrence of depressive symptoms. Our aim was to investigate the prevalence and risk factors of PSDS with adjustments for the previously mentioned prestroke factors. Methods: 420 consecutive patients with an acute clinical symptomatic transient ischemic attack or cerebral infarction were eligible for enrolment in this study. The presence of PSDS was rated by the Hospital Anxiety and Depression Scale 6–8 weeks after stroke. The relation between (pre-) stroke factors and PSDS was assessed with multivariate regression analysis. Results: The prevalence of PSDS was 13% and did not differ between stroke subtype or first-ever/ever occurrence of stroke. Higher degree of post-stroke handicap was related to PSDS (OR = 5.39; 95% CI = 2.40–12.08) and more functional independence had a protective effect on PSDS (OR = 0.88; 95% CI = 0.77–1.00). Conclusions: This is the largest study that investigated the prevalence and risk factors of PSDS by carefully excluding patients with depressive symptoms shortly before stroke. PSDS were not related to lesion side or location, but to the degree of post-stroke handicap and functional independence. Early detection of PSDS and their risk factors might help to predict long-term outcome and could promote early interventions of (behavioral) rehabilitation treatment strategies.