Neuropsychiatric systemic lupus erythematosus (NP-SLE) is a common complication of systemic lupus erythematosus (SLE), and clinical interventions are of only limited efficacy despite relatively high prevalence. Such complications have been studied extensively, but the pathoetiology of NP-SLE has not yet been elucidated. Diagnosis of NP-SLE focuses primarily on psychological manifestations, and the underlying mechanisms leading to neuropsychiatric complications remain unknown. To address potential changes in brain function before NP-SLE development, we used resting-state functional magnetic resonance imaging (MRI) to compare regional brain activity in SLE patients versus matched controls. We report that regional activity in cerebellum and in areas of the default mode network are attenuated in patients with SLE, and moreover individual alterations in cerebellar activity correlated positively with the disease activity index. These findings provide direct evidence that significant alteration of brain function, resembling that observed in patients with NP-SLE, is already present in SLE patients without neuropsychiatric complications, highlighting the need for early evaluation and intervention in SLE patients. Furthermore, the disease activity rating correlated with regional functional alterations in the cerebellum, suggesting that the cerebellum could play a role in the pathogenesis of NP-SLE. Hum Brain Mapp, 2011. © 2010 Wiley-Liss, Inc.