Apolipoprotein A-I (apoA-I) plays an important role in clearing cholesterol and phospholipids from peripheral tissues - a process known as reverse cholesterol transport. This results in the formation of high-density lipoprotein (HDL), the 'good cholesterol'. ApoA-I is structurally dynamic, making it well-adapted to bind various amounts of lipid molecules. However, this characteristic also contributes to its amyloidogenic propensity in atherosclerosis and hereditary amyloidosis. Herein, we crystallised and solved the structure of lipid-free apoA-I. The structure reveals that apoA-I is a four-helix bundle at the N-terminal domain, with a 'hinge' region connecting the third and fourth helices, whereas the C-terminal domain is disordered and unresolved in the structure. Such a compact conformation of apoA-I was not observed in the previously solved structures as this hinge region appears to be opened up and extended in the previous C-terminal truncation structure (PDB ID: 3r2p)1. Moreover, MD simulations of the previously solved C-terminal truncation structure revealed that apoA-I dimerises by domain-swapping and appears more elongated in solution compared to its crystal structure, as confirmed by our small-angle X-ray scattering (SAXS) data. Although the apoA-I WT is relatively stable and not prone to forming fibrils, structural perturbations such as methionine oxidation or various naturally occurring mutations were shown to cause fibril formation in full-length apoA-I within 24 h under a slightly acidic pH. Furthermore, limited proteolysis and hydrogen-deuterium exchange coupled with NMR showed that the rigid fibril core only comprises the N-terminal portion of the protein sequence even in full-length apoA-I fibrils. This amyloidogenic N-terminal region is normally protected by the interactions within the helical bundle, thus destabilisation of the helical bundle conformation may expose this region promoting aberrant interactions. Further investigations are required to elucidate the structural details of this destabilised conformation and how that nucleates fibril formation.