Alzheimer's disease is a neurodegenerative disorder characterized by the accumulation of amyloid plaques in the brain. This amyloid primarily contains amyloid-beta (Abeta), a 39- to 43-aa peptide derived from the proteolytic cleavage of the endogenous amyloid precursor protein. The 42-residue-length Abeta peptide (Abeta(1-42)), the most abundant Abeta peptide found in plaques, has a much greater propensity to self-aggregate into fibrils than the other peptides and is believed to be more pathogenic. Synthetic human Abeta(1-42) peptides self-aggregate into stable but poorly-ordered helical filaments. We determined their structure to approximately 10-A resolution by using cryoEM and the iterative real-space reconstruction method. This structure reveals 2 protofilaments winding around a hollow core. Previous hairpin-like NMR models for Abeta(17-42) fit well in the cryoEM density map and reveal that the juxtaposed protofilaments are joined via the N terminus of the peptide from 1 protofilament connecting to the loop region of the peptide in the opposite protofilament. This model of mature Abeta(1-42) fibrils is markedly different from previous cryoEM models of Abeta(1-40) fibrils. In our model, the C terminus of Abeta forms the inside wall of the hollow core, which is supported by partial proteolysis analysis.