BACKGROUND: Approximately one third of all patients who have been successfully treated for cancer suffer from chronic cancer-related fatigue (CCRF). Effective and easily accessible interventions are needed for these patients. OBJECTIVE: The current paper reports on the results of a 3-armed randomized controlled trial investigating the clinical effectiveness of two different guided web-based interventions for reducing CCRF compared to an active control condition. METHODS: Severely fatigued cancer survivors were recruited via online and offline channels, and self-registered on an open-access website. After eligibility checks, 167 participants were randomized via an embedded automated randomization function into: (1) physiotherapist-guided ambulant activity feedback (AAF) therapy encompassing the use of an accelerometer (n = 62); (2) psychologist-guided web-based mindfulness-based cognitive therapy (eMBCT; n = 55); or (3) an unguided active control condition receiving psycho-educational emails (n = 50). All interventions lasted nine weeks. Fatigue severity was self-assessed using the Checklist Individual Strength -- Fatigue Severity subscale (primary outcome) six times from baseline (T0b) to six months (T2). Mental health was self-assessed three times using the Hospital Anxiety and Depression Scale and Positive and Negative Affect Schedule (secondary outcome). Treatment dropout was investigated. RESULTS: Multiple group latent growth curve analysis, corrected for individual time between assessments, showed that fatigue severity decreased significantly more in the AAF and eMBCT groups compared to the psycho-educational group. The analyses were checked by a researcher who was blind to allocation. Clinically relevant changes in fatigue severity were observed in 66% (41/62) of patients in AAF, 49% (27/55) of patients in eMBCT, and 12% (6/50) of patients in psycho-education. Dropout was 18% (11/62) in AAF, mainly due to technical problems and poor usability of the accelerometer, and 38% (21/55) in eMBCT, mainly due to the perceived high intensity of the program. CONCLUSIONS: Both the AAF and eMBCT interventions are effective for managing fatigue severity compared to receiving psycho-educational emails. TRIAL REGISTRATION: trialregister.nl NTR3483; http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=3483.

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