PURPOSE: Symptom monitoring has demonstrated improved outcomes in patients with cancer, including quality of life, resource utilization, ability to continue treatment, and survival. The use of disease-specific patient-reported outcome (PRO) measures facilitates symptom monitoring. While the MD Anderson Symptom Inventory–Lung Cancer (MDASI-LC), a PRO measure of symptom burden in lung cancer, is psychometrically validated for use in patients with NSCLC, its content validity has not been verified through direct patient input. Our purpose is to describe the symptom experience of patients with NSCLC and to confirm that the MDASI-LC contains the key symptoms specific to NSCLC from the patient perspective. METHODS: Patients with NSCLC described their symptom experience in single qualitative interviews. Content analysis was used to define the content domain for a PRO measure of NSCLC symptom burden. RESULTS: Participants (N = 40) had a mean age of 66.1 years (standard deviation, 10.9 years); 60.0% were male, 77.5% were White, and 56.4% had stage IV disease. Thirty-two symptoms were described, with 6 reported by ≥ 20% of participants. Symptom variations were noted by treatment modality but not by stage of disease. Patients with NSCLC commonly reported shortness of breath, cough, distress, fatigue, pain, and constipation. In patients receiving chemotherapy, treatment-related symptoms, including neuropathy and sore mouth, were commonly noted. The presence of these symptoms resulted in interference with daily activities, relationships, life plans, treatment adherence, and mood. CONCLUSION: The symptoms included in the MDASI-LC are important components of the content domain of an NSCLC symptom burden measure. The presence of these symptoms affect daily life and, therefore, is of clinical consequence.