Background <p>Easily accessible clinical warning signals of liver cirrhosis for optimal management in people living with HIV/HBV co-infection remains limited. Using proteomic techniques, a risk prediction model for liver cirrhosis through the screening of differentially expressed proteins (DEPs) in people living with HIV/HBV coinfection was developed.</p> Methods <p>Quantitative liquid chromatography-mass spectrometry (LC–MS) was used to identify DEPs in plasma collected from HIV/HBV co-infected patients with or without liver cirrhosis. The annotation information of DEPs were obtained by mapping identified proteins to the Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes(KEGG), and Disease Ontology(DO) databases. Differential expression levels of plasma L-selectin(CD62L) were validated in HIV/HBV co-infected patients.</p> Results <p>Proteomic profiling of 13 matched patient pairs with HIV/HBV coinfection revealed 111 differentially expressed proteins (DEPs) associated with liver cirrhosis. Functional analysis showed significant enrichment in immune processes and the Complement and Coagulation Cascades pathway, underpinning the chronic inflammatory and fibrotic aspects of the disease. A diagnostic signature derived from these DEPs was developed, with a model containing IGHV5-37 and L-selectin showing high predictive value. Critically, the elevated plasma level of L-selectin in cirrhosis was confirmed in a separate validation cohort of 90 patients, underscoring its clinical relevance.</p> Conclusions <p>Our findings demonstrate that cirrhosis in HIV/HBV coinfected patients is characterized by a specific plasma proteomic profile. From this profile, we derived and validated a diagnostic model, highlighting L-selectin as a key validated biomarker. This model holds significant promise for development into a clinical assay to improve the detection and management of liver disease in this high-risk population.</p> Clinical trial <p>Not applicable</p>