Physiological assessment is challenging in patients with multivessel disease (MVD) with a chronic total occlusion (CTO) and may result in inappropriate treatment decisions. We report herein, for the first time to our knowledge, on the dynamic changes of the instantaneous wave-free ratio in the CTO collateral donor artery before and after coronary artery bypass grafting (CABG). Our case highlights the paramount importance of collateral circulation when interpreting invasive indices of coronary stenosis severity to guide decision-making for CABG in MVD patients with a CTO. This may be particularly relevant to reduce the risk of early graft failure in patients with MVD undergoing CABG.