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Amyloids are implicated in neurodegenerative diseases. Fibrillar aggregates of the amyloid-β protein (Aβ) are the main component of the senile plaques found in brains of Alzheimer’s disease patients. We present the structure of an Aβ(1-42) fibril composed of two intertwined protofilaments determined by cryoelectron microscopy (cryo-EM) to 4.0 Å resolution, complemented by solid-state nuclear magnetic resonance (NMR) experiments. The backbone of all 42 residues and nearly all sidechains are well resolved in the EM density map, including the entire N terminus, which is part of the cross-β structure resulting in an overall “LS”-shaped topology of individual subunits. The dimer interface protects the hydrophobic C termini from the solvent. The unique staggering of the nonplanar subunits results in markedly different fibril ends, termed “groove” and “ridge,” leading to different binding pathways on both fibril ends, which has implications for fibril growth.