Purpose: To explore the associations between (improvement in) fatigue and (improvement in) clinical and cognitive factors in patients with chronic widespread pain (CWP), participating in multidisciplinary rehabilitation treatment. Methods: Data were used from baseline, 6 and 18 months of follow-up during a prospective cohort study of 120 CWP patients who completed multidisciplinary rehabilitation treatment. Cross-sectional and longitudinal relationships were analyzed between fatigue, clinical (i.e. pain, interference of pain and depression) and pain related cognitive factors (i.e. negative emotional cognitions, active cognitive coping, and control and chronicity beliefs). Results: Higher levels of pain, interference of pain, depression, negative emotional cognitions, and negative control and chronicity beliefs were associated with a higher level of fatigue. Improvement in depression was related to improvement in fatigue. Conclusions: In CWP patients, worse clinical status, and dysfunctional pain-related cognitions are associated with a higher level of fatigue. Our results suggest that improvement in depression might be a mechanism of improvement in fatigue. Furthermore, improvement in fatigue seems to be independent of improvement in pain related cognitions. Targeting fatigue in multidisciplinary pain treatment may need specific strategies.Implications for RehabilitationImprovement in depression may be a mechanism of change to improve the level of fatigue in CWP.Improvement in dysfunctional (pain related) cognitions seems to be independent of improvement in fatigue.Targeting fatigue in multidisciplinary treatment may need specific strategies (e.g. additional interventions focusing on reducing fatigue and specific attention to improvement of sleep).