OBJECTIVES: Few studies have examined thrombosis in systemic lupus erythematosus (SLE), none have included Asian-Americans, and most have had small sample sizes. We analysed risk factors for thrombosis in a large, multi-ethnic SLE cohort. METHODS: We studied 1930 SLE subjects, including Caucasians, African-Americans, Asian-Americans and Hispanics. Data were derived from questionnaires and medical records. Documented history of thrombosis was the primary outcome. Explanatory variables included age at SLE diagnosis, gender, ethnicity, disease duration, smoking, antiphospholipid antibody (aPL) status, nephritis and specific medications. RESULTS: Smoking (OR 1.26, p = 0.011), longer disease duration (OR 1.26 per 5 years p = 0.027 x 10(-7)), nephritis (OR 1.35, p = 0.036), aPL positivity (OR 3.22, p<10(-9)) and immunomodulating medication use (OR 1.40, p = 0.011) were statistically significant risk factors for thrombosis. Younger age at SLE onset was protective (OR 0.52 for age </=20, p = 0.001). After adjusting for disease severity and incorporating propensity scores, hydroxychloroquine use remained significantly protective for thrombosis (OR 0.62, p = 4.91 x 10(-4)). CONCLUSIONS: This study confirms that older age at onset, longer disease duration, smoking, aPL positivity, history of nephritis and immunomodulating medication use are risk factors for thrombosis in SLE. These data are the first to confirm in a large and ethnically diverse SLE cohort that hydroxychloroquine use is protective for thrombosis.