The acetylcholinesterase (AChE) inhibitor donepezil is also a σ1 receptor agonist. We examined whether donepezil binds to σ1 receptors in the living human brain after a single oral administration. Dynamic positron emission tomography (PET) data acquisition using the selective σ1 receptor ligand [11C]SA4503 was performed to evaluate quantitatively the binding of [11C]SA4503 to σ1 receptors in eight healthy male volunteers. Each subject had a PET scan before and after receiving a single dose of donepezil (5 or 10 mg). The binding potential of [11C]SA4503 was calculated. Doses of 5 mg and 10 mg donepezil bound to σ1 receptors in the human brain with occupancies of ~60% and ~75%, respectively, in a dose-dependent manner. This study demonstrated that donepezil binds to σ1 receptors in the living human brain at therapeutic doses. Therefore, σ1 receptors may be implicated in the pharmacological mechanism of donepezil in the human brain.