Neuropsychiatric Systemic Lupus Erythematosus (NP-SLE) is associated with cerebral abnormalities, but their relation to the inflammatory and ischemic clinical phenotypes is unknown. We performed a retrospective structural brain study within a large, clinically well-defined patient cohort of NP-SLE patients (inflammatory and ischemic) and non-NP-SLE patients. Patients with inflammatory, but not ischemic, NP-SLE showed lower grey matter and white matter volumes, and higher White Matter Hyperintensity volumes compared to non-NP-SLE patients. Brain abnormalities were also associated with the complement system. In conclusion, only inflammatory NP-SLE showed more severe structural brain abnormalities, and these were associated with a specific complement component.