BACKGROUND: Although studies show that cancer patients consider fatigue as an important problem, few, if any, studies have quantified the impact of fatigue on overall quality of life (QoL) in cancer patients. In the present study, we evaluated the relative impact of different QoL domains/subscales, including fatigue, on overall QoL in cancer patients preceding radiotherapy. PATIENTS AND METHODS: Sixty-four patients with lung or breast cancer selected for high-dose radiotherapy on the primary tumour completed the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire. Multivariate models were fitted to define the impact of QLQ-C30 subscales, including fatigue, on overall QoL. RESULTS: Of all QLQ-C30 subscales, fatigue showed by far the strongest univariate correlation with overall QoL (r = -0.76, P < 0.001); correlations for functioning subscales (r = 0.44-0.55) and symptom subscales (r = -0.31 to -0.45) were considerably lower. In multivariate analyses, adjusting for potential confounders, fatigue was the only subscale that independently contributed to overall QoL (standardized regression coefficient-0.57, P < 0.001). CONCLUSION: Our results indicate that, of all QoL domains/subscales, fatigue is by far the predominant contributor to patient-perceived overall QoL in both lung and breast cancer patients preceding high-dose radiotherapy.