Present technologies for proteomics typically require analytes be in the liquid phase. Some analytes such as fibrous proteins, membrane proteins, and protein aggregates are intrinsically insoluble or have greatly decreased solubility in aqueous systems. This is often circumvented by surfactants, chaotropes, pH control, solid phase proteolysis (on-pellet digestion), and more.1 However, recent literature has demonstrated the capabilities of a new class of chemical system, called ionic liquids, to dissolve intractable biomaterials containing insoluble biopolymers such as cellulose, and keratin.2 Ionic liquids (ILs) are salts with low melting points, typically composed of an organic unsymmetrical cation (such as N,N’-dialkylimidazolium) and various anions such as chloride, acetate, tetrafluoroborate, etc.3 Previous research has been centred around the dissolution of protein or polysaccharide material for purposes other than analysis, such as bio-material preparation, and bio-catalysis.4 The use of ILs in bioanalytical chemistry of proteins has lagged behind, and of the few published investigations, most employ ILs in dilute aqueous solutions, where ILs are employed as cationic surfactants.5 There is evidence to suggest that concentrated or neat ILs have unique properties and therefore may allow researchers to dissolve previously insoluble protein analytes. This has the potential to increase depth and robustness of sample preparation, and facilitate the analysis of intractable samples. Previous research using concentrated ILs for this purpose is sparse and there is a need to systematically investigate the structure-activity relationship between an IL’s cation and anion structure, and its capacity to solubilise proteins. As an initial foray into the efficacy of these solvents for proteomics, bovine serum albumin was dissolved in a series of synthesised ionic liquids and aliquots were removed over time to monitor the dissolution progression by light microscopy, and the maintenance of the proteins primary structure by SDS-PAGE. The results confirm that hydrophilic ILs showed the best solubilisation capacity and that higher temperatures (in a restricted sense) improved solubility of the protein. However, higher temperatures and longer reaction times caused a reduction in the apparent molecular weight of the protein. Some preliminary investigations into the nature of BSA’s modified primary structure after ionic liquid treatment have been conducted using LC-MS/MS based proteomics, but require further optimisation to be conclusive. Hence, for the present, researchers should exercise caution when using ionic liquids for protein analysis, until the full scope and limitations are known, an aspect we are presently investigating.