Alzheimer's disease (AD), the most common neurodegenerative disorder, is characterized by neurofibrillary tangles, synaptic impairments, and loss of neurons. Oligomers of -amyloid (A) are widely accepted as the main neurotoxins to induce oxidative stress and neuronal loss in AD. In this study, we discovered that fucoxanthin, a marine carotenoid with antioxidative stress properties, concentration dependently prevented A oligomer-induced increase of neuronal apoptosis and intracellular reactive oxygen species in SH-SY5Y cells. A oligomers inhibited the prosurvival phosphoinositide 3-kinase (PI3K)/Akt cascade and activated the proapoptotic extracellular signal-regulated kinase (ERK) pathway. Moreover, inhibitors of glycogen synthase kinase 3 (GSK3) and mitogen-activated protein kinase (MEK) synergistically prevented A oligomer-induced neuronal death, suggesting that the PI3K/Akt and ERK pathways might be involved in A oligomer-induced neurotoxicity. Pretreatment with fucoxanthin significantly prevented A oligomer-induced alteration of the PI3K/Akt and ERK pathways. Furthermore, LY294002 and wortmannin, two PI3K inhibitors, abolished the neuroprotective effects of fucoxanthin against A oligomer-induced neurotoxicity. These results suggested that fucoxanthin might prevent A oligomer-induced neuronal loss and oxidative stress via the activation of the PI3K/Akt cascade as well as inhibition of the ERK pathway, indicating that further studies of fucoxanthin and related compounds might lead to a useful treatment of AD.