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Because of a rise in incidence and more effective treatments, the prevalence of patients with metastatic cancer is increasing fast. When palliative treatment is aimed at maintaining or improving patients’ quality of life, knowledge about severe fatigue is clinically relevant because of its debilitating effect, but at present this information is lacking.This study investigated the prevalence of severe fatigue in patients with various incurable cancers and whether severe fatigue increased with further treatment lines and differed between various cancers and treatment modalities. In addition, a relationship between severe fatigue and other symptoms was examined.Patients were asked to fill in the Checklist Individual Strength, European Organization of Research and Treatment of Cancer–Quality of Life Questionnaire C30, and the McGill Pain Questionnaire during palliative anticancer treatment, and hemoglobin levels were collected.Of all participating patients (n = 137), 47% were severely fatigued. Patients who received first line of treatment were significantly less often severely fatigued (40%) compared with patients who received further lines (60%). Significantly more severe fatigue was observed when patients had more pain, dyspnea, appetite loss, nausea, vomiting, and constipation.During the phase of palliative anticancer treatment, fatigue was the most common symptom, nearly half of the patients had severe fatigue increasing with further treatment lines. Various treatment-related symptoms were related to more severe fatigue.As severe fatigue is significantly related to other symptoms of cancer and its treatment, the screening and treatment of these cancer-related symptoms should be more stringent, as they might negatively influence each other.