Antiphospholipid syndrome (APS) is a heterogeneous autoimmune disease with persistent antiphospholipid antibodies. This study aimed to identify unrecognized APS subgroups from multicenter cohorts (n = 760, training: n = 415
validation: n = 345). Patients are stratified through unsupervised K-means clustering analysis. Prognostic outcomes are evaluated using Kaplan-Meier survival analyses. Proteomic analysis is conducted on primary APS patients (n = 36) and healthy controls (n = 12). Key molecule insulin-like growth factor 1 is validated using ELISA. Three clusters are identified. Cluster 1 (n = 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 (n = 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 (n = 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-based distinction within thrombotic APS. Three APS subgroups display unique clinical and molecular characteristics, and marked difference in prognostic outcomes.