Among all the analytical techniques available for epitope mapping studies, hydrogen–deuterium exchange mass spectrometry (HDX-MS) is usually the fastest and easiest to carry out. We present here the epitope mapping of three distinct monoclonal antibody (mAb) candidates targeting the same antigen, an interleukin receptor. The goal is to establish the binding mode of these mAbs, and explain possible differences observed for in vitro binding and in vivo function.