Manual inspection of multi-pass data revealed high-quality peptide ions not captured by default HDMS E processing methods. Consequently, we developed a novel ion mobility processing strategy capable of better handling multi-pass LC-MS data. Interestingly, the use of 1-pass and multi-pass cIM routines resulted in unique peptide populations, with their combined output being 31 to 222% higher than previous generation SYNAPT G2-Si instrumentation. Thus, we propose a novel HDX-MS workflow with integrated cIM that has potential to improve data quality of complex samples in the future.