In light of recent evidence implicating the upregulation of outward K + current in mediating several forms of neuronal apoptosis, we tested the hypothesis that such an upregulation might specifically contribute to the pathogenesis of β-amyloid peptide (Aβ)-induced neuronal death. Exposure to Aβ fragment 25-35 (20 μM) or 1-42 (20 μM) enhanced the delayed rectifier K + currentI K , shifting its activation voltage relationship toward hyperpolarized levels and increasing maximal conductance, but did not affect the transient K + currentI A or charybdotoxin-sensitive BK current. ReducingI K by adding the channel blocker tetraethylammonium (TEA, 5 mM) or raising extracellular K + to 25 mM attenuated Aβ-induced neuronal death, even in the presence of nifedipine or gadolinium to block associated increases in Ca 2+ influx. TheI A blocker 4-aminopyridine (4-AP, 5 mM) and the Cl − channel blocker anthracene-9-carboxylic acid (ACA, 500 μM) were not neuroprotective. These data raise the intriguing possibility that manipulations aimed at reducing outward K + current may provide an approach to reducing neuronal degeneration in patients with Alzheimer's disease.