The amyloid β-protein precursor (APP) is proteolytically cleaved to generate the amyloid β-protein (Aβ), the principal constituent of senile plaques found in Alzheimer's disease (AD). In addition, Aβ in its oligomeric and fibrillar forms have been hypothesized to induce neuronal toxicity. We and others have previously shown that APP can be cleaved by caspases at the C-terminus to generate a potentially cytotoxic peptide termed C31. Furthermore, this cleavage event and caspase activation were increased in the brains of AD, but not control, cases. In this study, we show that in cultured cells, Aβ induces caspase cleavage of APP in the C-terminus and that the subsequent generation of C31 contributes to the apoptotic cell death associated with Aβ. Interestingly, both Aβ toxicity and C31 pathway are dependent on the presence of APP. Both APP-dependent Aβ toxicity and C31-induced apoptotic cell death involve apical or initiator caspases-8 and -9. Our results suggest that Aβ-mediated toxicity initiates a cascade of events that includes caspase activation and APP cleavage. These findings link C31 generation and its potential cell death activity to Aβ cytotoxicity, the leading mechanism proposed for neuronal death in AD.