Cryptococcal meningitis has become the largest cause for the death of infectious diseases in the central nervous system infectious disease worldwide. Most patients with cryptococcal meningitis have AIDS, autoimmune diseases, hematologic malignancies, and some other relevant diseases. It is mainly caused by infection with or . Although the relationship between cryptococcal meningitis and autoimmune diseases, such as systemic lupus erythematosus, has been recognized, little has been studied about it. Furthermore, with the use of glucocorticoids and immunosuppressants, the incidence of cryptococcal meningitis is increasing year by year. Cryptococcal meningitis accounts for 15% of HIV-related deaths globally, compared with little research on HIV-negative cryptococcal diseases. A 54-year-old female patient with gingival bleeding was admitted to the Department of Neurology at the Second Xiangya Hospital of Central South University. The patient subsequently developed a series of central nervous system symptoms such as headache, ischemic stroke, and epilepsy. The number of thrombocytes was at 4×10/L, antinuclear antibody was (+), antihuman globulin was (++), globulin IgG anticardiolipin antibody IgG, IgA, and IgM was positive, lupus anticoagulant was strong positive, antibody against β2 glycoprotein 1 IgM >841 AU/mL with elevated cerebrospinal fluid (CSF) pressure. The CSF India ink staining was positive, CSF was cultured cryptococcus neoformans. Antiphospholipid syndrome (APS) and cryptococcal neoformans meningitis were diagnosed. After active antifungal therapy and control of APS, the patient still had a serial of complications including high CSF pressure, persistent positive India ink staining, refractory electrolyte disturbance, hemolytic anemia recurs, heart failure, and finally death. No cases of the combination of the two diseases have been reported, and this case of cryptococcal meningitis with APS may provide a new direction to the diagnosis and treatment for this kind of disease.