To evaluate the frequency and risk factors of acute psychosis in a large cohort of patients with systemic lupus erythematosous (SLE). To identify clinical and laboratory variables useful in differentiating acute psychosis as a primary manifestation of central nervous system (CNS) from corticosteroid induced psychosis. Five hundred and thirty seven consecutive patients with SLE were studied, with follow-up ranging from 4 to 8.8 years. A standardized medical history, neurological, rheumatologic, and psychiatric examinations and serologic testing were performed in all patients. The type and frequency of risk factors associated with acute psychosis as a primary manifestation of CNS system and corticosteroid induced psychosis was determined using multivariate regression with automatic backward stepwise selection. We identified acute psychosis in 89 of 520 (17.1%) SLE patients. Psychosis primary to CNS involvement was diagnosed in 59 of these patients, corticosteroid induced psychosis in 28 and primary psychotic disorder not related to SLE or medication in two patients. Psychosis secondary to SLE at disease onset occurred in 19 patients and was associated with disease activity (p = 0.001; OR = 2.4; CI = 1.5-6.2). Psychosis during follow-up of SLE was observed in 40 patients and associated with positive antiphospholipid antibodies (p = 0.004; OR = 3.2; CI = 1.9-4.5) and less frequently with renal (p = 0.002; OR = 1.9; CI = 0.0-0.6) and cutaneous (p = 0.04; OR = 1.1; CI = 0.0-0.8) involvement. We identified 28 patients with 38 episodes of psychosis associated with corticosteroid therapy. All the patients had severe active disease and ten of these patients had hypoalbuminemia when psychosis developed. At the time of psychotic event, all the patients were taking prednisone in doses varying from 0.75 to 1 mg/kg day(-1). Psychosis resolved after tapering prednisone down in all patients. Acute psychosis related to SLE was observed in 11.3% of our cohort. Recurrence of primary psychosis was associated with other CNS manifestations related to SLE.