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Ephrin type-B receptor 2 (EphB2) is a member of the receptor tyrosine kinase family and plays an important role in learning and memory functions. In patients with Alzheimer's disease (AD) and in mouse models of AD, a reduction in the hippocampal EphB2 level is observed. It was recently reported that normalization of the EphB2 level in the dentate gyrus rescues memory function in a mouse model of AD, suggesting that drugs that restore EphB2 levels may be beneficial in the treatment of AD. Amyloid β (Aβ) oligomers, which are believed to be key molecules involved in the pathogenesis of AD, induce EphB2 degradation through their direct binding to EphB2. Thus, compounds that inhibit the binding of Aβ oligomers to EphB2 may be beneficial. Here, we screened for such compounds from drugs already approved for clinical use in humans. Utilizing a cell-free screening assay, we determined that dihydroergotamine mesilate, bromocriptine mesilate, cepharanthine, and levonorgestrel inhibited the binding of Aβ oligomers to EphB2 but not to cellular prion protein, another endogenous receptor for Aβ oligomers. Additionally, these four compounds did not affect the binding between EphB2 and ephrinB2, an endogenous ligand for EphB2, suggesting that the compounds selectively inhibited the binding of Aβ oligomers to EphB2. This is the first identification of compounds that selectively inhibit the binding of Aβ oligomers to EphB2. These results suggest that these four compounds may be safe and effective drugs for treatment of AD.