Thirty-seven patients with systemic lupus erythematosus underwent complete clinical and laboratory evaluations, including antiphospholipid antibodies and lupus anticoagulant, magnetic resonance imaging of the brain, and transesophageal echocardiography. Cerebrovascular disease manifested as stroke, transient ischemic attack, or cerebral infarcts in patients with nonfocal neurologic deficits was detected in 19 patients (51%), and significant left-sided valvular heart disease in 25 (68%). Valve vegetations, valve thickening, valve regurgitation, and lupus anticoagulant antibody occurred 2 to 3 times more often in patients with than without cerebrovascular disease (all p < or =0.04) and were the only independent predictors of cerebrovascular disease (odd ratios 5.3 to 10.6, all p < or =0.03). Thus, valvular heart disease probably exacerbated by hypercoagulability appears to be a source of embolic ischemic brain injury and cerebrovascular disease.