Atypical manifestations of chronic graft-versus-host disease (cGVHD) can affect both the central nervous system (CNS) and peripheral nervous systems presenting with diverse clinical and paraclinical features. These manifestations are often difficult to distinguish from other neurologic conditions, particularly those resulting from drug toxicity and opportunistic infections. To date, only rough diagnostic criteria for these rare manifestations have been proposed. The objective of this study was to contribute additional data to the existing literature and to develop more specific diagnostic criteria for cGVHD affecting the CNS. Based on the 2020 National Institutes of Health report on atypical cGVHD and an interdisciplinary approach, we propose 3 distinct forms of CNS-cGVHD: vasculitis-like, demyelinating, and meningoencephalitis. We have developed a scoring system to categorize the likelihood of CNS-cGVHD as unlikely, possible, or probable. The score was applied in a retrospective review of all patients who underwent allo-HSCT at the University Hospital of Regensburg between 2007 and 2022, focusing on those with suspected CNS-cGVHD by analyzing the neurologic symptoms, diagnostic findings, and clinical course of all patients. Out of 770 patients who underwent allo-HSCT, 19 (2.5%) were identified with possible (n = 6) or probable (n = 13) cGVHD affecting the CNS. These included 12 patients with meningoencephalitis, 4 patients with vasculitis-like, and 1 patient with demyelinating cGVHD; 2 patients presented with “mixed phenotype” showing symptoms of 2 entities. First-line treatment comprised corticosteroids for most cases (n = 18), with 8 patients receiving at least 2 agents concomitantly as part of the initial therapeutic regimen. A clinical response to first-line therapy was observed in 12 patients. A median of 2 lines of therapy were administered for treatment of CNS-cGVHD, with 14 patients showing a response to immunosuppressive therapy (IST), and 5 patients showing no response to IST. The 6-month and 1-year overall survival following CNS-cGVHD onset was 78% for both. The cause of death was attributed at least in part to CNS-cGVHD in 4 patients, extraneurologic cGVHD in 2 patients, cardiovascular disease in 1 patient, cerebral hemorrhage in 1 patient, and relapse of acute myeloid leukemia in 1 patient. Eight of the 19 patients experienced long-lasting (>6 months) neurologic sequelae. Diagnosing atypical cGVHD remains a significant challenge and necessitates interdisciplinary discussions between neurologists and hematologists on a case-by-case basis. We propose new diagnostic criteria aimed at standardizing the diagnostic process for CNS manifestations of cGVHD. With an incidence of 2.5%, CNS-cGVHD is a rare but serious complication after allo-HSCT, associated with long-term neurologic sequelae; early diagnosis and early IST may improve neurologic outcomes. Our modified scoring system is aimed at diagnosing this entity as a basis for larger, multicenter studies.