In a study concerning a group of cancer patients undergoing radiotherapy three research questions were addressed. (1) Is fatigue a valid criterion for depression in these somatically ill patients? (2) What is the 'cause-and-effect' relation between fatigue and depression? (3) To what extent are fatigue and depression related to patients' quality of life. A heterogeneous sample of cancer patients (n = 250) were interviewed before treatment, 2 weeks after treatment and 9 months later. Fatigue was measured using the MFI, a self-report instrument covering five dimensions of fatigue. Depression was assessed with the non-somatic items of the CES-D. Quality of life had to be indicated on a Cantrill ladder. Fatigue and depression do not follow the same course over time. Just after radiotherapy, fatigue had either increased or remained stable, depending on the dimension under consideration. Depression, in contrast, decreased. Nine months later fatigue had decreased, whereas levels of depression remained stable. Concurrent relations between fatigue and depression were mostly moderate. There was no strong evidence for a cause-and-effect relationship between depression and fatigue. Depression showed highest concurrent relationships with quality of life, especially before treatment. Prospectively, depression and the dimension of physical fatigue were the main predictors for quality of life. Fatigue is not a valid criterion for depression in these patients. Nor is there a strong cause-and-effect relationship. Both depression and physical fatigue are relevant to patients' quality of life.