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This study aimed to identify unrecognized APS subgroups from multicenter cohorts (<jats:italic>n<\/jats:italic> = 760, training: <jats:italic>n<\/jats:italic> = 415; validation: <jats:italic>n<\/jats:italic> = 345). Patients are stratified through unsupervised K\u2010means clustering analysis. Prognostic outcomes are evaluated using Kaplan\u2010Meier survival analyses. Proteomic analysis is conducted on primary APS patients (<jats:italic>n<\/jats:italic> = 36) and healthy controls (<jats:italic>n<\/jats:italic> = 12). Key molecule insulin\u2010like growth factor 1 is validated using ELISA. Three clusters are identified. Cluster 1 (<jats:italic>n<\/jats:italic> = 320, 42.1%) is completely consisted of females (100%), with predominant occurrence of pregnancy morbidity (88.8%) but low incidences of thrombocytopenia (18.4%) and thrombosis (15.0%), and a favorable prognosis. Cluster 2 (<jats:italic>n<\/jats:italic> = 309, 40.7%) is predominantly female (99.4%) and characterized by high thrombosis (85.8%) and thrombocytopenia (46.6%), low pregnancy morbidity (13.6%), and poor prognosis. Cluster 3 (<jats:italic>n<\/jats:italic> = 131, 17.2%) is predominantly male (99.2%), exhibiting highest thrombosis (96.2%) and moderate thrombocytopenia (32.8%), with worst prognosis. Immunological and proteomic analyses clearly differentiated three clusters. This study reveals a distinct difference between obstetric and thrombotic APS, and a sex\u2010based distinction within thrombotic APS. Three APS subgroups display unique clinical and molecular characteristics, and marked difference in prognostic outcomes.<\/jats:p>","DOI":"10.1002\/advs.202415291","type":"journal-article","created":{"date-parts":[[2025,2,18]],"date-time":"2025-02-18T14:43:57Z","timestamp":1739889837000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Identification of Three Distinct Subgroups in Antiphospholipid Syndrome: Implication for Sex Differences and Prognostic Outcomes from a Multicenter Study"],"prefix":"10.1002","volume":"12","author":[{"given":"Chen","family":"Chen","sequence":"first","affiliation":[{"name":"Department of Rheumatology and Immunology Peking University People's Hospital  Beijing 100044 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ao","family":"Zhang","sequence":"additional","affiliation":[{"name":"School of Information and Communication Engineering Beijing University of Posts and 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