Background: T790M is a major cause of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) resistance, but the clinical significance of T790M disappearance is unknown. Case Report: We report 3 cases of pulmonary adenocarcinoma which did not respond to EGFR-TKI retreatment even with T790M disappearance. T790M mutations were detected in the pleural effusions after the tumors had acquired EGFR-TKI resistance. T790M mutations disappeared from cancer cells in the pleural effusion after a break from the treatment drug and cytotoxic agent administration. However, no therapeutic effect was obtained despite EGFR-TKI reinitiation. Conclusions: Responsiveness to EGFR-TKI might not be restored in some cases, although the disappearance of T790M mutations is confirmed.