OBJECTIVES: The benefits of systemic treatment NSCLC patients are greater control of the symptoms and improvement of HRQoL. The study aimed to assess the impact on daily living and HRQoL of the symptoms of advanced NSCLC. METHODS: Observational study with prospective follow-up (basal and 6-8 week visit). 257 patients with stage IIIB NSCLC, with pleural/pericardial effusion or stage IV NSCLC, about to initiate second-line treatment were included by 32 hospitals in Spain. Demographic and clinical data relating to Lung Cancer Symptom Scale (LCSS) and the lung-specific Functional Assessment of Cancer Therapy questionnaire (FACT-L) were collected. Specific questions evaluating impact of symptoms on patient daily life were included. RESULTS: By gender, 79.4% of patients were men, the mean (SD) age was 63.7 (10.0) years. ECOG 1 was presented by 56.4% and 38.9% of patients at the basal and final visits respectively. 93% (n=240) of patients received chemotherapy in first line and 78.2% received targeted therapies (mainly erlotinib) as second line therapies. Twenty-six percent of patients demonstrated disease progression at the final visit but FACT-L scores showed no difference between visits; 48.8% of patients reported unchanged perceived health status and 28.1% reported an improvement. Patient and physician LCSS scores showed 86.4% of patients reported more symptoms than their physician but that there were no differences between visits.  The impact of symptoms on daily life was slightly lower at the final than the basal visit. Statistically significant differences were observed between disease progression and the impact of cough (p = 0.040) and pain (p = 0.02), and also between the LCSS scale score (p <0.01). CONCLUSIONS: Stability and improvement of some symptoms corresponded to lower impact of the same symptoms on patients. The number and type of symptoms were related to HRQoL and the degree to which patient daily life was affected.