Background: Families of children with rare diseases (i.e., not more than 5 out of 10,000 people are affected) are often highly burdened with fears, insecurities and concerns regarding the affected child and its siblings. Although families caring for children with rare diseases are known to be at risk for mental disorders, the evaluation of special programs under high methodological standards has not been conducted so far. Moreover, the implementation of interventions for this group into regular care has not yet been accomplished in Germany. The efficacy and cost-effectiveness of a family-based intervention will be assessed. Methods/design: The study is a 2x2 factorial randomized controlled multicenter trial conducted at 17 study centers throughout Germany. Participants are families with children and adolescents affected by a rare disease aged 0 to 21 years. Families in the face-to-face intervention CARE-FAM, online intervention WEP-CARE or the combination of both will be treated over a period of roughly 6 months. Topics discussed in the interventions include coping, family relations, and social support. Families in the control condition will receive treatment as usual. The primary efficacy outcome is parental mental health, measured by the Structured Clinical Interview for DSM-IV (SCID-I) by blinded external raters. Further outcomes will be assessed from the parents’ as well as the children’s perspective. Participants are investigated at baseline, 6, 12 and 18 months after randomization. In addition to the assessment of various psychosocial outcomes, a comprehensive health-economic evaluation will be performed. Discussion: This paper describes the implementation and evaluation of two family-based intervention programs for Children Affected by Rare Disease and their Family’s Network (CARE-FAM-NET) in German standard care. A methodologically challenging study design is used to reflect the complexity of the actual medical care situation. This trial could be an important contribution to the improvement of care for this highly burdened group. Trial registration: German Clinical Trials Register: DRKS00015859 (registered 18 December 2018) and ClinicalTrials.gov: NCT04339465 (registered 8 April 2020). Protocol Version: 15 August 2020 (Version 6.1). Trial status: Recruitment started on 1 January 2019 and will be completed on 31 March 2021. © 2020, The Author(s).