The ability to design detergents that are suitable for protein analysis by mass spectrometry (MS) represents an on-going challenge in the field of native MS. Desirable detergent characteristics include charge-reducing properties and low gas-phase stabilities of complexes formed with proteins. In this work, the gas-phase properties of oligoglycerol detergents (OGDs) are optimized by fine tuning of their molecular structure. Furthermore, a tandem mass spectrometry (MS/MS) approach is presented that estimates the gas-phase properties of detergents simply by studying the dissociation behaviour of protein-detergent complexes (PDCs) formed with the soluble protein β-lactoglobulin (BLG).