Objective Cancer-related fatigue (CRF) has an important impact on the quality of life in breast (BC) and colorectal (CRC) cancer patients. Until now only a limited number of prospective studies have investigated the effect of adaptive salutogenic mechanisms on CRF, in addition to the biological influences. The aim of our study was to assess a possible effect of autonomic Regulation (aR) and self-regulation (SR) on CRF and distress in long-term survivors. Therefore, questionnaires on aR and SR were combined with the Hospital Anxiety and Depression Scale (HADS-D) and the Cancer Fatigue Scale (CFS-D), including three subscales. Method In total, 95 BC and 51 CRC patients as well as 120 healthy controls (C) had participated in the initial survey in 2000/2001. On average 6 years later, 62 BC, 17 CRC patients and 87 C could be followed up (number of females: 62 for BC, 11 for CRC, 60 C). Forty-one further participants were deceased (14 BC, 25 CRC and 2 C). During the follow-up, patients were requested to complete the CFS-D, HADS-D, aR and SR scales and to determine their Karnofsky-Index (KPI) through self-evaluation. Multiple regression analysis was used to evaluate the influence of aR and SR as well as age, gender and diagnosis groups. Results On average, disease duration of cancer patients was 10.1 years at a KPI of 93.3% at the follow-up. High aR values showed a significant effect 6 years after initial evaluation, reducing cancer fatigue with β =−0.66 (KI: −0.92 to −0.39; p β =−0.20 (KI: −0.31 to −0.09; p β =−0.21 (KI: −0.31 to −0.11; p β =−2.39 KI: −4.45 to −0.34; p =0.022), anxiety ( β =−0.87, KI: −1.65 to −0.10; p =0.028) and depression with β =−0.87 (KI: −1.36 to −0.38; p =0.001). Conclusion AR had an independent positive effect on anxiety, global and cognitive fatigue. Self-regulation showed an independent influence on fatigue, anxiety and depression-related symptoms. The connection between these parameters is still unclear and awaits further elucidation.