While combined 1-pass/multi-pass peptide mapping provided the highest number of peptides identified for all assessed targets, there remained some sequence segments which not analysed (e.g., TMD3 of SMO). Despite the effective increase in the overall peak capacity when using the combined 1pass/multi-pass cIM routines, there are further gains to be achieved. Increased peak capacity in combination with other strategies, such as use of alternative proteases and optimised quench buffer compositions , is likely the route to deriving optimal sequence coverage for challenging targets such as IMPs. It is possible that the increased peak capacity afforded by cIM will be most beneficial when studying more complex samples (e.g., multi-subunit protein complexes). Nevertheless, the HDX-MS workflow proposed in this manuscript still holds potential to improve HDX-MS analyses for any target protein with both previously optimised and non-optimised experimental conditions.