Background <p>Non-small cell lung cancer (NSCLC), which is one of the most common cancer types, has caused lots of deaths to patients worldwide. Aside from the surgical treatment or chemotherapy, the third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), Osimertinib, is used as a treatment for patients with non-small cell lung cancer. However, the cardiotoxicity related to Osimertinib, which is rarely reported, is still a controversial issue to be discussed.</p> Case presentation <p>A 70-year-old Taiwanese female diagnosed with lung adenocarcinoma had been with Osimertinib treatment for two years. During admission for a routine lung cancer staging workup, she developed acute-onset dyspnea with pulmonary edema. She did not present with any infection-related symptoms. The echocardiography revealed global hypokinesis, while a thallium scan showed no evidence of myocardial infarction. Her symptoms resolved gradually following the withdraw of Osimertinib.</p> Conclusion <p>We report a case of acute decompensated heart failure in a patient with lung cancer who had been receiving Osimertinib therapy for two years. To the best of our knowledge, this represents the longest the interval reported between initiation of Osimertinib and the onset of cardiotoxicity. The diagnosis of Osimertinib-related heart failure was made by exclusion of the other etiologies, and the patient’s clinical symptoms recovered after cessation of Osimertinib for one week. Although the cause of Osimertinib-related cardiotoxicity is still unclear, regular cardiac examination of the patients should be considered.</p>