Tumefactive demyelinating lesions (TDLs) are rare, large demyelinating lesions of the central nervous system that can mimic brain tumours in radiological appearance. They have been observed across multiple demyelinating diseases. Previous studies have suggested that antibody profiles may correlate with distinct clinical or imaging characteristics, but detailed comparisons between antibody-defined subgroups in TDLs remain limited.We retrospectively analysed 30 patients with confirmed TDLs. Demographic, clinical, imaging and laboratory data were collected, and patients were stratified by myelin oligodendrocyte glycoprotein (MOG) and N-methyl-D-aspartic acid receptor (NMDAR) antibody results. Lesion characteristics were evaluated on brain MRI, and outcomes were assessed by modified Rankin Scale at last follow-up. Statistical comparisons were made between antibody-positive and antibody-negative subgroups.Among TDLs subgroups, MOG+ patients had elevated cerebrospinal fluid white cell counts and showed greater lesion volume reduction on follow-up MRI than MOG- patients. NMDAR+ patients showed elevated levels of systemic inflammatory markers compared with NMDAR- counterparts. Regardless of antibody status, most TDLs patients responded well to immunotherapy, with 86.7% achieving a favourable outcome.TDLs represent a heterogeneous inflammatory syndrome. MOG and NMDAR antibodies influence the clinical and laboratory characteristics of TDL patients but have limited impact on prognosis.Copyright © Author(s) (or their employer(s)) 2025. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ Group.