Lumacaftor-Ivacaftor (LI) is indicated for the treatment of Cystic Fibrosis (CF) in patients age 12 years and older who are homozygous for the F508del mutation in the CFTR gene. LI discontinuation has been associated with the development of new thoracic-region pain (TRP) in some CF patients. Recognition of this adverse effect can change the approach used to manage CF patients who stop LI. The goal of this case study is to describe case features of patients experiencing TRP upon withdrawal of LI and to share strategy for mitigating the severity/occurrence of TRP in these patients. Three patients were reviewed who had to discontinue LI. All three patients experienced pain and discomfort following discontinuation of the medication. CF providers should be aware of these adverse effects and should educate patients accordingly. Also, intensification of airway clearance in patients requiring withdrawal of LI may theoretically lessen the risk of thoracic pain.