Objectives <p>To investigate the clinical and laboratory features of Sjögren’s syndrome-associated autoimmune liver disease (SS-ALD) patients and identify potential risk and prognostic factors.</p> Methods <p>SS patients with or without ALD, who visited Tongji Hospital between the years 2011 and 2021 and met the 2012 American College of Rheumatology (ACR) classification criteria for Sjögren’s syndrome, were retrospectively enrolled. The clinical and laboratory data of the enrolled patients, including autoimmune antibodies, were collected and analyzed with principal component analysis, correlation analysis, LASSO regression, and Cox regression.</p> Results <p>A total of 117 SS-ALD patients were confirmed out of 568 SS patients. Compared to SS-non-ALD patients (<i>n</i> = 451), SS-ALD patients exhibited more severe involvement of the hepatic and hematologic systems, albeit with less pronounced typical SS symptoms. Disease activity was higher in SS-ALD patients, as indicated by elevated ESR, CRP, and IL-6 levels, particularly in the SS-overlap subgroup. Furthermore, SS-AIH patients without AIH-specific autoantibody testing or with negative testing results had higher AST and ALT levels than those who were autoantibody-positive. Our predictive model, incorporating IgG, IgM, AST, GGT, ALT, and C4, effectively identified ALD complications in SS patients, achieving an AUC of 0.924. Additionally, a grimmer prognosis was associated with higher baseline AST and ALT levels.</p> Conclusions <p>SS-ALD patients often manifest with an insidious onset and atypical SS symptoms, yet frequently exhibit severe systemic involvement, intense inflammatory and immune responses, and a poor prognosis. To improve the clinical outcomes in SS-ALD patients, regular monitoring, early identification, and active treatment should be applied.</p> <p><Table Float="No" ID="Taba"> <tgroup cols="2"> <colspec align="left" colname="c1" colnum="1" /> <colspec align="left" colname="c2" colnum="2" /> <tbody> <row> <entry align="left" nameend="c2" namest="c1"> <p><b>Key Points</b></p> <p>• <i>The study provided a detailed profile of clinical and laboratory features of SS-ALD and SS-non-ALD patients, contributing to a predictive model of ALD complications in SS patients</i></p> <p>• <i>SS-ALD patients manifested with an insidious onset but exhibited severe systemic involvement, robust inflammatory and immune responses, and poor prognosis</i></p> <p>• <i>SS-AIH patients without available testing for AIH-specific autoantibodies or with negative results demonstrated worse liver function, thus routine screening for autoimmune liver antibodies is recommended in SS patients</i></p> <p>• <i>More severe baseline liver function status was associated with poorer therapeutic responses to routine medications, so early detection and timely intervention are essential for SS patients</i></p> </entry> </row> </tbody> </tgroup> </Table></p>