Background: Medically unexplained symptoms (MUS) are highly prevalent and pose a burden both on patients and on health care. In a pilot study psychosomatic therapy delivered by specialised therapists for patients with MUS showed promising results with regard to patient's acceptability, feasibility and effects on symptoms. The aim of this study is to establish whether psychosomatic therapy by specialised psychosomatic exercise therapists is cost- effective in decreasing symptoms and improving functioning in patients who frequently consult their general practitioner (GP) with MUS. Methods: A randomised effectiveness trial with an economic evaluation in primary care with 158 patients aged 18 years and older who are frequently consulting their GP with MUS. Patients will be assigned to psychosomatic therapy in addition to usual care or usual care only. Psychosomatic therapy is a multi-component and tailored intervention, aiming to empower patients by applying psycho-education, relaxation techniques, mindfulness, cognitive approaches and/or graded activity. Patients assigned to the psychosomatic therapy receive 6 to 12 sessions of psychosomatic therapy, of 30-45 min each, delivered by a specialised exercise or physical therapist. Primary outcome measure is patient-specific functioning and disability, measured with the Patient-Specific Functional Scale (PSFS). Secondary outcome measures are symptom severity, consultation frequency and referrals to secondary care, patient satisfaction, quality of life and costs. Assessments will be carried out at baseline, and after 4 and 12 months. An economic evaluation alongside the trial will be conducted from a societal perspective, with quality-adjusted life years (QALYs) as outcome measure. Furthermore, a mixed-methods process evaluation will be conducted. Discussion: We expect that psychosomatic therapy in primary care for patients who frequently attend the GP for MUS will improve symptoms and daily functioning and disability, while reducing consultation frequency and referrals to secondary care. We expect that the psychosomatic therapy provides value for money for patients with MUS.