This study investigated the association between anti-Ro52 antibodies, cerebral small vessel disease (CSVD) burden, and neurological outcomes in acute ischemic stroke (AIS) patients.We conducted a retrospective study of 127 AIS patients admitted between June 2017 and June 2024. CSVD burden was quantified using a composite score (range: 0-3) based on three neuroimaging markers. Severe CSVD was defined as a score >1. Neurological function was evaluated using the modified Rankin Scale (mRS), where a score >2 at admission and 3 months post-stroke indicated poor outcomes. After propensity score matching, 38 anti-Ro52-positive patients were compared with 38 anti-Ro52-negative controls. Multivariate logistic regression analyses were performed to assess independent associations.Multivariate analysis revealed that anti-Ro52 positivity, advanced age, and hypertension were independently associated with severe CSVD burden (all p < 0.05). Furthermore, anti-Ro52 positivity, higher NIHSS scores, and severe CSVD burden were independently correlated with poor neurological function at admission and 3 months post-stroke (all p < 0.05).Our findings demonstrate that anti-Ro52 antibodies are independently associated with severe CSVD burden in AIS patients. Moreover, both anti-Ro52 positivity and CSVD burden are significantly associated with worse neurological outcomes. Our study suggests that anti-Ro52 antibodies may influence stroke severity through the development and progression of CSVD.Copyright © 2025. Published by Elsevier Inc.