Systemic rheumatic disorders affect multiple organ systems. Seizures are among the most common neurological manifestation and occasionally can be the presenting symptom. This article reviews the literature on the mechanisms underlying seizures in systemic rheumatic disorders and predisposing factors, including vascular disease (e.g., prothrombotic state, anticardiolipin antibody, emboli, vasculitis), antineuronal antibodies, immune complexes, cytokines, metabolic disorders, infection, and therapy. Diagnostic and therapeutic strategies must be individualized for both the disorder and the patient.