Background: Cancer-related fatigue (CRF) affects a majority of patients (pts) with symptoms lasting up to several years after finishing therapy. These symptoms lead to decreased health related quality of life. Fatigue during treatment for colorectal cancer is common, but poorly understood and can affect compliance with post-surgical cancer therapy. We examined the fatigue levels during first-line chemo- or radio-chemotherapy protocols, which were supported by a pharmaceutical mistletoe preparation (Iscador®Qu) (181patients). We compared the outcome to a parallel control group (143 patients), which did not receive this supportive care treatment. Methods: The medical records of 324 patients with non-metastasized colorectal cancer (UICC stage I - III), which were obtained from hospitals and resident physicians, were assessed. The documented treatment decision by chemo- or radio-chemotherapy supported by mistletoe interventions was followed for a median treatment period of 8.6 months. During the post-surgical treatment period the patients were diagnosed twice for the presence of fatigue symptoms by structural interviews carried out by physicians. Results: At the end of the median treatment period, 16/181 patients (8.8%) were diagnosed with CRF in the supportive care group and 86/143 (60.1%) in the chemo – or radio-chemotherapy group without supportive mistletoe medication. Multivariable-adjusted ORs provided evidence for a chance to improve CRF by supportive mistletoe medication compared to chemo- or radio-chemotherapy alone over the time of treatment. The OR = 10.651 (95% CI 5.09-22.28; p < 0.001) declined from the first visit to OR = 0.054 (95 CI 0.02-0.13; p < 0.001) at the end of therapy. Furthermore, 14 confounding factors for risk assessment of CRF were compared by means of forest plots. It turned out that the hospital versus office-based treatment and the co-morbidity/inflammation represent independent but important determinants for fatigue levels. Conclusion: The clinically used mistletoe medication (Iscador®Qu) is the first candidate to be included in a supportive care modus into chemo- or chemo-radiotherapy protocols for colorectal patients to improve CRF without discernable toxicities.