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Cognitive-behavior therapy (CBT) leads to a reduction of fatigue and pain in chronic fatigue syndrome. The processes underlying the reduction in pain have not been investigated. Recently, it was shown that increased self-efficacy, decreased focusing on symptoms, increased physical functioning, and a change in beliefs about activity contribute to the decrease in fatigue.The present study has 2 objectives: (1) to determine the relationship between the reduction of fatigue and pain during CBT; (2) test to what extent the model for change in fatigue is applicable to the reduction in pain.One hundred forty-two patients meeting United States centers for Disease Control and Prevention criteria for chronic fatigue syndrome, currently reporting pain, and starting CBT were included. A cross-lagged analysis was performed to study the causal direction of change between pain and fatigue. Pain and process variables were assessed before therapy, 3 times during CBT, and after therapy. Actual physical activity was also assessed. The model was tested with multiple regression analyses.The direction of change between pain and fatigue could not be determined. An increase in physical functioning and decrease in focusing on symptoms explained 4% to 14% of the change in pain.Pain and fatigue most probably decrease simultaneously during CBT. Pain reduction can partly be explained by a reduction of symptom focusing and increased physical functioning. Additional, yet unknown cognitive-behavioral factors also play a role in the reduction of pain.