The p75 neurotrophin receptor (p75 NTR) is a known mediator of β-amyloid (Aβ)-induced neurotoxicity implicated in Alzheimer’s disease (AD). Here, we demonstrate that death receptor 6 (DR6) binds to p75 NTR and is a component of the p75 NTR signaling complex responsible for Aβ-induced cortical neuron death. Cortical neurons isolated from either DR6 or p75 NTR null mice are resistant to Aβ-induced neurotoxicity. Blocking DR6 function in cortical neurons by anti-DR6 antibodies that block the binding of DR6 to p75 NTR receptor complex or by a dominant negative DR6 construct lacking the cytoplasmic signaling death domain attenuates Aβ-induced caspase 3 activation and cell death. DR6 expression is upregulated in AD cortex and correlates with elevated neuronal death. Targeting the disruption of the DR6/p75 NTR complex to prevent Aβ cytotoxicity represents a new approach for the treatment of neurodegenerative disorders such as AD.