BACKGROUND The use of electronic nicotine delivery systems (ENDS), commonly referred to as electronic cigarettes (e-cigarettes), involves inhaling a mixture of heated nicotine, glycerin, propylene glycol, and flavorings. There has been increasing concern about the harm of long-term use of e-cigarettes, including an association with the development and progression of lung cancer. This report describes a 51-year-old male former cigarette smoker with an 11-year history of e-cigarette use (vaping) presenting with an aggressive advanced squamous cell carcinoma of the lung, which was fatal. CASE REPORT A 51-year-old man with type 2 diabetes, hypertension, a 10-pack-year smoking history, and 11 years of e-cigarette use presented with hemoptysis, weight loss, chest discomfort, and worsening dyspnea. Initial imaging revealed a large left upper-lobe mass. Transesophageal echocardiography (TEE) showed a large tumor thrombus in the left atrium. Biopsy confirmed poorly differentiated squamous cell carcinoma (SCC). He was stabilized and discharged, but returned 2 weeks later with worsening symptoms. Imaging showed significant tumor progression. Bronchoscopy revealed worsening airway compression. A Y-shaped stent was placed, with clinical improvement. He began systemic therapy as an outpatient, but deteriorated rapidly and died 3 months following diagnosis. CONCLUSIONS This case illustrates an aggressive presentation of squamous cell lung carcinoma with intracardiac tumor thrombus in a relatively young former smoker with prolonged e-cigarette use. While causality cannot be established, the case highlights a potential association between ENDS use and malignancy. Further research is needed to investigate the long-term effects of e-cigarettes and their possible role in lung cancer development and progression.