BACKGROUND: Internet interventions offer advantages that especially cancer survivors who suffer from fatigue could benefit from. Given the growing number of such patients, Internet interventions could supplement and strengthen currently available health care. OBJECTIVE: This paper describes the design and analysis plan that will be used to study 2 Internet interventions aimed at reducing severe fatigue in cancer survivors: a mobile ambulant activity feedback therapy supported through a weekly email by a physiotherapist and a weekly Web- and mindfulness-based cognitive therapy supported online by a psychologist. The data resulting from this trial will be used to (1) investigate the effectiveness, (2) investigate potential mediators of these interventions, and (3) explore participant characteristics that can predict the effect of these interventions. METHODS: A 3-armed randomized controlled trial is proposed that compares both Internet interventions with an active control condition that solely consists of receiving psycho-educational emails. The intervention period is 9 weeks for all 3 conditions. Six months after baseline, participants in the control condition can choose to follow 1 of the 2 experimental Internet interventions. Outcomes are measured in terms of fatigue severity, mental health, and self-perceived work ability. All are Web-assessed at baseline, 2 weeks after the intervention period, and at 6 and 12 months after baseline. Fatigue severity, mindfulness, physical activity, expectations and credibility of the intervention, therapeutic working alliance, sleep quality, and sense of control over fatigue are assessed 3 times during the intervention period for identifying mediators of the interventions. Recruitment is performed nationally throughout the Netherlands through patient organizations and their websites, newspapers, and by informing various types of health professionals. All participants register at an open-access website. We aim at including 330 cancer survivors who have finished curative-intent cancer treatment at least 3 months previously, and have been suffering from severe fatigue ever since. All cancer types are included. A detailed analysis plan is described to address the research questions, which allows for individual variation, and fully exploits the longitudinal design. RESULTS: Recruitment started in April 2013 and will proceed until April 2015. CONCLUSIONS: This paper describes a systematic trial design for studying 2 different interventions for chronic cancer-related fatigue in order to gain insight into the effectiveness and mediators of the interventions. This design will also be used to identify predictors for the interventions' effect on fatigue. By publishing our hypotheses and analysis plan before completion of data collection, this paper is a first step in reporting on this trial comprehensively. TRIAL REGISTRATION: The Netherlands National Trial Register (NTR3483). (Archived by WebCite at http://www.webcitation.org/6NWZqon3o).