Objective: To investigate whether it was possible to detect the presence and different levels of naturally occurring anti-β-amyloid (Aβ) antibodies in the CSF of patients with AD and age-matched controls by employing a sensitive ELISA. Background: Immunization with preaggregated amyloid β-peptide (Aβ1-42) and administration of antibodies against Aβ into amyloid precursor protein APPV717F- transgenic mice (an animal model of AD) have recently been reported to dramatically reduce amyloid plaque deposition, neuritic dystrophy, and astrogliosis, most likely by enhancing Aβ clearance from brain. Methods: A sensitive ELISA was performed to detect levels of naturally occurring anti-Aβ antibodies in the CSF of patients with AD and age-matched controls. Additionally, an immunoprecipitation assay was performed to confirm that naturally occurring anti-Aβ antibodies also exist in the human blood. Result: Naturally occurring antibodies directed against Aβ were found in the CSF and plasma of patients with AD and healthy control subjects. Moreover, CSF anti-Aβ antibody titers are significantly lower in patients with AD compared with healthy control subjects. Conclusion: Naturally occurring antibodies directed against Aβ exist in human CSF and plasma. The CSF anti-Aβ antibody titers may be helpful in better understanding the effects of future immunologic therapies for AD.