Objective: To study whether standard cognitive behavioral therapy (CBT) and a shorter, interpersonal oriented cognitive behavioral therapy (I-CBT) can improve physical function and fatigue in patients diagnosed with mild to moderate chronic fatigue syndrome (CFS) in a multidisciplinary fatigue clinic. Design: Consecutively 236 participants 18-62 years old meeting the Centre of Decease Control, CDC 1994 criteria, with a subsample also fulfilling the Canadian criteria for CFS, were randomly allocated to one of three groups. Two intervention groups received either 16 weeks of standard CBT or 8 weeks of I-CBT vs. a waiting-list control group (WLC). Primary outcome was the subscale Physical Function (PF) from SF-36 (0-100). Secondary outcome was amongst others fatigue measured by Chalder Fatigue Questionnaire (CFQ) (0-33). Outcomes were repeatedly measured up to 52 weeks from baseline. Results: The additional effect relative to baseline at post-intervention for SF-36 physical function was 14.2 (95% CI 7.9-20.4 p < 0.001) points higher for standard CBT and 6.8 (0.5-13.2 p = 0.036) points higher for I-CBT compared with the control group. The additional effect relative to baseline at post-intervention for fatigue was 5.9 (95% CI 0.5-10.5 p = 0.03) points lower for standard CBT compared with the control group but did not differ substantially for I-CBT 4.8 (95% CI -0.4 to 9.9 p = 0.07). The positive change in physical function persisted at 1-year follow-up for both treatment groups, and for standard CBT also in fatigue. The two intervention groups did not differ significantly in self-reported physical function and fatigue at the 1-year follow-up. No serious adverse reactions were recorded in any of the groups during the trial period. Interpretation: A 16-week standard, individual CBT intervention improves physical function and fatigue in CFS outpatients with mild to moderate disease. A shorter 8-week I-CBT program improves physical function. Both treatments are safe, and the effect persist 1 year after baseline. Clinical Trial registration: ClinicalTrials.gov, Identifier: NCT00920777, registered June 15, 2009. REK-project number: 4.2008.2586, registered April 2, 2008. Funding: The Liaison Committee for Education, Research and Innovation in Central Norway.

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