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Background Anorexia nervosa (AN) is a serious psychiatric illness that begins most of the time during adolescence. An early and efficacious intervention is crucial to minimize the risk of the illness becoming chronic and to limit the occurrence of comorbidities. There is a global consensus on optimal treatment for adolescents suffering from AN: international guidelines recommend single-family therapy that involves the patient and his/her family. Several family therapy approaches have been developed to date. However, these approaches, which imply a direct questioning of intrafamilial dynamics, are not suitable for all patients and families, and the rates of dropout or poor response to treatment remain quite high. A modality of family therapy has been adapted to AN, known as multi-family therapy (MFT), which consists in bringing together several families whose children suffers from the same illness. Objectives of the present randomized clinical trial are to evaluate whether the implementation of MFT in a multi-disciplinary treatment program for adolescents with AN is at least as efficacious as the use of systemic single-family therapy (SFT), with respect to the evolution of body mass index and other clinical outcomes 12 and 18 months after the start of treatment. A cost-efficiency analysis will also be conducted. Methods One hundred fifty patients meeting the inclusion criteria will be randomly assigned to one of the two treatment groups. Patients and their families will receive 10 sessions of therapy spread over 12 months. Body weight, eating disorder and other psychopathology-related symptoms, quality of family relationships, and family satisfaction with treatment will be evaluated during the treatment and at an 18 months follow-up. A cost-efficiency analysis will also be carried out. Discussion We hypothesize that MFT is at least as efficacious as SFT, but at a lesser cost. The identification of possible preferential indications for each technique could help the improvement of therapeutic indications for adolescents suffering from AN and contribute to the earliness of intervention, which is associated with a better outcome. Trial registration ClinicalTrials.gov, NCT03350594 . Registered on 22 November 2017. IDRCB number 2016-A00818-43. Electronic supplementary material The online version of this article (10.1186/s13063-019-3347-y) contains supplementary material, which is available to authorized users.