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Objectives While thrombosis is a hallmark of antiphospholipid syndrome (APS), recurrent or refractory thrombotic events raise concern for additional contributing factors. Coexisting immunodeficiency in systemic lupus erythematosus (SLE) patients may alter both the clinical course and response to therapy.Methods We present a case of a patient with SLE and APS who experienced multiple refractory thrombotic events alongside recurrent bacterial and fungal infectionsResults A 17-year-old female was diagnosed with SLE in 2007, initially presenting with autoimmune hemolytic anemia (AIHA), lymphopenia, proteinuria, and positive anti-dsDNA, anti-Sm, and anticardiolipin antibodies. After a flare in 2016, mycophenolate mofetil (MMF) was started, leading to remission. From 2018, she suffered recurrent severe infections, including sinusitis, mastoiditis requiring mastoidectomy, Nocardia brain abscess, and Fusarium bloodstream infection, resulting in MMF discontinuation. Each infectious episode was accompanied by thrombotic events (deep vein thrombosis, pulmonary thromboembolism) despite anticoagulation. Persistent CD4+ lymphopenia (15/μL), intermittent severe neutropenia, and normal immunoglobulin levels were noted. Nitroblue tetrazolium test showed normal neutrophil reactive oxygen species production. Whole exome sequencing identified heterozygous variants in LAT (linked to Immunodeficiency 52) and NCF1 (associated with Chronic Granulomatous Disease type 1), both reported in SLE as well. In May 2025, for the first time outside active infection, the patient developed extensive DVT and pulmonary embolism following an AIHA flare managed with methylprednisolone pulses and MMF reintroduction. A broad antiphospholipid antibody panel (aCL, anti-β2GPI, anti-prothrombin, and anti-annexin V of IgG, IgM, IgA classes), was negative, as was genetic thrombophilia testing. Considering endothelial dysfunction driven by increased neutrophil extracellular trap formation, MMF was stopped, colchicine added, and anticoagulation switched to fondaparinux. The patient is currently stable, with no new thrombosis and no signs of active SLE except compensated AIHA.Conclusions This case highlights a rare overlap of autoimmunity, immunodeficiency, and refractory thrombosis, underscoring diagnostic and therapeutic challenges of this rare overlap.