Here, using both 1-pass and multi-pass cIM routines, we evaluated Cyclic IMS performance when analysing challenging IMP targets in the HDX-MS context. Using four model IMP samples (i.e., frizzled class GPCR smoothened receptor (SMO), secondary active transporter XylE, ATP binding cassette transporter MsbA, and the heterotrimeric SecYEG complex), we benchmarked Cyclic IMS performance relative to previous generation SYNAPT G2-Si instrumentation and report its enhanced performance.