We developed an HX-MS2 strategy that supports the acquisition of CID-generated fragment ions alongside their peptide precursors. The approach enables true auto-validation of HX data by mining the rich set of deuterated fragments, using the extra dimension of data to simultaneously confirm the peptide ID and authenticate (even correct) MS1-based deuteration calculations. The high redundancy provided by the fragments generates an opportunity to determine the confidence of deuterium calculations using a combinatorial strategy. The approach requires DIA-based acquisition methods that are available on most MS platforms, making the switch to HX-MS2 straightforward. Considerable time is saved through auto-validation and more importantly, more complex samples can now be characterized and at higher throughput, as illustrated in a drug binding analysis of the ultralarge kinase DNA-PKcs, isolated directly from mammalian cells.