Dementia with Lewy bodies (DLB) is a common subtype of dementia in the elderly. DLB is neuropathologically characterized by the presence of Lewy bodies and Lewy neurites, both of which are composed of α-synuclein. Although α-synuclein was initially considered to be an exclusively intracellular protein, it has been found to be secreted into biological fluids. α-Synuclein in biological fluids such as cerebrospinal fluid (CSF) and blood has been discussed as a potential biomarker of DLB and α-synuclein-related disorders, because α-synuclein is characteristically accumulated in the brain of patients with these disorders. The α-synuclein level in CSF has been examined by several investigators, and the majority of studies have shown a reduction in CSF α-synuclein level in DLB and α-synuclein-related disorders. Discrepant findings of studies of plasma α-synuclein level in patients with DLB have been reported. Because the level of α-synuclein stored in red blood cells is considerably high, blood contamination and haemolysis during sample collection and processing should be considered as a confounding factor for quantification of α-synuclein. Here, the recent progress in the studies of α-synuclein as a biomarker of DLB and their potential clinical applications are reviewed.