Alzheimer´s disease (AD) is characterized by progressive accumulation of the beta-amyloid peptide (Aβ) in the brains of affected individuals. Increased Aβ levels are thought to play a central role in neuronal dysfunction and neurodegeneration in AD. Aβ spontaneously undergoes aggregation, giving rise to oligomers, protofibrils and β-sheet rich amyloid fibrils. Aβ fibrils are present in the senile plaques found in AD brains. Oligomers, protofibrils and fibrils have all been shown to be neurotoxic in vitro and currently a major issue in the AD field is elucidating which are the major neurotoxic species in vivo. Physiological candidates to affect Aβ aggregation in vivo are thus of considerable interest in terms of our understanding of the pathogenesis of AD and of developing novel approaches to prevent Aβ-induced neurotoxicity. Apolipoprotein A-I (apoA-I) is naturally present in the cerebrospinal fluid (CSF), probably participating in cholesterol homeostasis required for brain development and neuronal plasticity. In this work we have investigated the interaction of apoA-I with Aβ and the possible role of apoA-I as a neuroprotector against Aβ-induced neurotoxicity. We show that apoA-I reversibly binds Aβ producing high molecular weight complexes. At higher molar ratios of Aβ to apoA-I, mainly long fibers were detected. In contrast, when the relative amount of apoA-I was increased, shorter and more disorganized fibers were predominant. When incubated with small unilamellar vesicles (SUVs), apoA-I did not diminish significantly Aβ-induced vesicle fusion. The effects of formation of Aβ/apoA-I complexes on neuronal survival were determined by examining the viabilities of rat cortical and hippocampal neuronal cultures incubated with Aβ alone or in the presence of apoA-I. Under these conditions, a moderate protection of apoA-I against the toxicity of Aβ (20 μM) was observed. Interestingly, even in the absence of Aβ, apoA-I increased neuronal survival in cultures in a dose-dependent manner. Our results suggest that apoA-I exhibits neuroprotective actions in general, and in particular against the neurotoxicity of Aβ.