INTRODUCTION: Cancer-Related Fatigue (CRF) is characterized as a distressing, persistent, and subjective sensation of physical, emotional, and/or cognitive exhaustion that is associated with cancer or its treatment. CRF is commonly observed in patients with cancer and a severely impairing symptom also in patients with the rare primary central nervous lymphoma (PCNSL). While its exact etiology remains unclear, elevated levels of tumor-induced inflammatory cytokines are believed to contribute to its development. Transcutaneous auricular vagal nerve stimulation (taVNS) is a non-invasive method to activate the vagal nerve through electrical stimulation of a vagally innervated area at the tragus. It has shown to modulate the immunsystem, to activate central arousal pathways and to reduce fatigue in autoimmune conditions. In this study, the effect of taVNS on the fatigue syndrome in patients with PCNSL will be investigated. METHODS: For this single-blinded, sham controlled, randomized controlled trial (RCT), 45 adult patients with PCNSL and fatigue in Multidimensional Fatigue Inventory (MFI20)-questionnaire after active treatment will be recruited and randomized to above-threshold-stimulation (A) sub-threshold-stimulation (B) or sham group (C). In Arm A, taVNS is perfomed on the left tragus (25 Hz, pulse width 250 µs,28 s on/32 s off,4 h/day). In Arm B, the patients will be asked to regulate the stimulator below perception threshold. In Arm C, the patients are initially shown how stimulation feels and then asked to decrease the intensity below perception threshold. They then take a non-functional sham-electrode home. Validated questionnaires data (MFI20, Beck Depression Inventory (BDI2), Short-form 26 (SF36), NeuroCogFx and Neurologic Assessment in Neuro-Oncology (NANO) and Hospital Anxiety Depression Scale (HADS)) will be collected at the beginning of the study and after 4 and 8 weeks. PLANNED OUTCOMES: This is the first clinical trial to assess if taVNS improves fatigue symptoms in patients with the primary CNS lymphoma. If taVNS improves fatigue in these patients, it will be a significant gain in quality of life. TRIAL REGISTRATION: The study was approved by the ethics committee (2024-368-f-S) and registered at the DRKS database (DRKS00036323).