Selective serotonin reuptake inhibitors (SSRIs) improve cognition in patients with stroke and increase the expression of brain-derived neurotrophic factor (BDNF) in the rat hippocampus. However, the effects of SSRIs on cognition and BDNF level in vascular dementia (VaD) patients are largely unknown. We performed an open-label study to investigate the effects of fluoxetine, a selective serotonin reuptake inhibitor, on mini-mental state examination (MMSE) score and serum BDNF level in VaD patients. Fifty VaD patients were randomly allocated to receive fluoxetine (20 mg/d; n = 25) or no fluoxetine (control group; n = 25) for 12 weeks. Both groups received secondary prevention of stroke. Baseline serum BDNF level correlated with MMSE score (r = 0.326, p = 0.021). MMSE score increased in the fluoxetine group (15.1 ± 3.0 at baseline vs. 16.1 ± 2.9 at week 12, p = 0.0004) but not in the control group (15.7 ± 2.6 vs. 15.8 ± 2.7, p = 0.566). Serum BDNF level increased in the fluoxetine group (21.2 ± 3.2 ng/ml at baseline vs. 25.7 ± 4.0 ng/ml at week 12, p < 0.001) but not in the control group (21.4 ± 5.8 ng/ml vs. 21.5 ± 6.9 ng/ml, p = 0.921). In the fluoxetine group, the increase in serum BDNF level correlated with the increase in MMSE score (r = 0.413, p = 0.04). The utility of SSRIs during cognitive recovery of VaD patients requires further investigation. BDNF may play an important role in cognitive recovery. (Trial registration: chictr.org, Identifier: ChiCTR-TRC-12002247).