The presence of anticardiolipin antibodies (ACLA) in multiple sclerosis (MS) patients has been reported, but there are some debates on the relationship between ACLA and MS. We assessed the clinical features of neuromyelitis optica spectrum disorders (NMOSD) patients with ACLA. A consecutive cohort of 480 subjects with NMOSD (n = 70), MS (n = 90) and control (n = 220) were analysed retrospectively. Patients' serum was tested by a dot-immunogold filtration assay for the presence of ACLA-IgG, IgM and IgA antibodies. In MS patients, 5 (5.6 %) of the 90 patients showed ACLA-IgG reactivity in the serum. In NMOSD patients, 32 (45.7 %) of the 70 patients showed ACLA reactivity in the serum, among which ACLA-IgG seropositivity was 45.7 % (32/70), ACLA-IgG + IgM seropositivity was 8.6 % (6/70), and ACLA-IgG + IgA seropositivity was 4.3 % (3/70). NMOSD patients were higher in ACLA-IgG (p < 0.0001) and ACLA-IgG + IgM (p = 0.006) than the MS patients. NMOSD patients had higher ACLA-IgG than the control patients (p < 0.0001). In comparison with the controls, the MS patients were lower in ACLA for IgG (p = 0.014) and IgM (p = 0.004). Seropositive ACLA patients increased in age (p = 0.013) and had higher D-dimer levels (DD) (p = 0.002) than the seronegative NMOSD patients. Furthermore, positive ACLA-IgG + IgM patients were increased in age (p = 0.001), had higher baseline EDSS (p = 0.001), antithrombin III activity (p = 0.04), and DD levels (p = 0.005) than the pure positive ACLA-IgG NMOSD patients. Patients with NMOSD had more occurrences of ACLA than patients with MS. NMOSD patients with positive ACLA-IgG + IgM had a worse outcome that may be associated with elder age and abnormal coagulation parameters in blood.