Quality of life (QOL) has been shown to improve with chemotherapy in patients with advanced non-small cell lung cancer (NSCLC), but the determinants of this improvement have not been thoroughly explored. Fifty consecutive NSCLC patients starting chemotherapy with measurable disease and with an Eastern Co-operative Oncology Group (ECOG) performance status of <or=2 were evaluated for change in QOL by European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ-C30). The status of global QOL before chemotherapy influenced the degree of change in physical functioning (F = 8.71, P =.001), global QOL (F = 23.82, P <.001), and fatigue (F = 7.92, P =.001), whereas age of the patient was again linked with the change in global QOL (F = 4.68, P =.014), and type of chemotherapy administration (1st vs. 2nd line) was associated with the change in fatigue (F = 7.82, P =.001). Our findings show that patient age and baseline QOL assessed by EORTC-QLQ-C30, but not ECOG performance status, may help predict the amount of improvement in certain aspects of QOL in patients with advanced NSCLC undergoing chemotherapy. Conversely, in this cohort, patients who are likely to have deteriorating QOL on chemotherapy may benefit from closer follow-up and nursing care to optimize supportive measures.