The cellular generation of toxic metabolites and subsequent detoxification failure can cause the uncontrolled accumulation of these metabolites in cells, leading to cellular dysfunction. Amyloid-beta protein (Abeta), a normal metabolite of neurons, tends to form toxic oligomeric structures that cause neurodegeneration. It is unclear how healthy neurons control the levels of intracellular oligomeric Abeta in order to avoid neurodegeneration. Using immunochemical and biochemical studies, we show that the Abeta-binding serine protease Omi is a stress-relieving heat-shock protein that protects neurons against neurotoxic oligomeric Abeta. Through its PDZ domain, Omi binds preferentially to neurotoxic oligomeric forms of Abeta rather than non-toxic monomeric forms to detoxify oligomeric Abeta by disaggregation. This specific interaction leads not only to mutual detoxification of the pro-apoptotic activity of Omi and Abeta-induced neurotoxicity, but also to a reduction of neurotoxic-Abeta accumulation. The neuroprotective role of Omi is further supported by its upregulation during normal neurogenesis and neuronal maturation in mice, which could be in response to the increase in the generation of oligomeric Abeta during these processes. These findings provide novel and important insights into the detoxification pathway of intraneuronal oligomeric Abeta in mammals and the protective roles of Omi in neurodegeneration, suggesting a novel therapeutic target in neurodegenerative diseases.