The asymptomatic nature of atherosclerosis is prompting the biomedical community to develop methods that can identify patients with high risk of cardiovascular incidents before any clinical symptoms develop. Current opinion is that oxidative modifications to circulating LDL particles (oxLDL) under inflammatory conditions are responsible for mediating fusion/aggregation events and conferring its atherogenicity. LDL particles are complex in nature, being composed of a hydrophobic outer layer of phospholipids wrapped by glycosylated Apo B-100 protein, and any of these biomolecules located at the surface of the particle may be a target of oxidative damage. The relevance, together or individually, of different modifications in oxLDL is not yet clear, with the additional challenge that the structural features inherent in each of the modification play a significant role in the complexity of setting up MS based strategies for their detection. Protocols based on mass spectrometry (MS) coupled with reverse phase LC were applied to the structural characterisation of LDL protein (Apo B-100) from normolipidemic individuals. Protein sequence coverage ≥70% was routinely achieved. In this work we describe the applicability of different MS scanning methods targeted towards the detection of oxidised amino acids, and modifications by oxidised phospholipids and sugar moieties, in providing information about the structural modifications in ApoB-100 protein from oxLDL and their location within the protein. Changes in these during oxidative stress and in diseased states are currently being investigated and correlated with lipid profile data. The development of advanced and targeted methods that allow the mapping of modifications in protein, lipid and glycan moieties of LDL particles by MS-based approaches is expected to provide a broader insight on the role that these modifications may have in the development of atherosclerosis.