Soluble fractalkine plays a distinctive role in the inflammatory processes of the nervous system; however, the role of soluble fractalkine in Alzheimer's disease (AD) has not yet been investigated. In the present study, we evaluated the levels of plasma soluble fractalkine in patients with mild cognitive impairment (MCI), patients with AD and healthy controls. We also investigated the changes in the levels of plasma soluble fractalkine in patients with AD. A total of 102 patients with cognitive impairment, including 51 patients with MCI, 51 patients with AD, and 57 healthy control subjects, were enrolled in this study. The Mini-Mental Status Examination (MMSE) was used to evaluate the severity of cognitive impairment in patients with MCI and AD. The levels of plasma soluble fractalkine were measured using a specific enzyme-linked immunosorbent assay. There were significant group differences in the levels of plasma soluble fractalkine between the MCI, AD, and control groups. Post hoc analyses revealed significant differences between the MCI and control groups, the AD and control groups, and the MCI and AD groups. The level of plasma soluble fractalkine was significantly greater in the patients with mild to moderate AD than in the patients with severe AD. In addition, there was a positive correlation between MMSE score and plasma soluble fractalkine level in the patients with AD. This study provides preliminary evidence that soluble fractalkine is involved in the pathogenesis of AD.