OBJECTIVE: To assess whether the risk of incident systemic lupus erythematosus (SLE) is associated with the use of combined oral contraceptives (COCs), because studies of the link between exogenous hormonal exposure and the risk of SLE have produced conflicting results. METHODS: We conducted a population-based nested case-control study among women ages 18-45 years, using the UK's General Practice Research Database. All incident cases of SLE from 1994-2004 (n = 786) were identified in the database and matched with up to 10 controls (n = 7,817) among women without SLE at the time of the case's diagnosis. RESULTS: The adjusted rate ratio (RR) of incident SLE associated with any use of COC was 1.19 (95% confidence interval [95% CI] 0.98-1.45), whereas with current use it was 1.54 (95% CI 1.15-2.07). The rate was particularly increased in current users who had only recently started COC use (RR 2.52, 95% CI 1.14-5.57) compared with longer-term current users (RR 1.45, 95% CI 1.06-1.99). The risk appeared to be particularly elevated with current exposure to first- or second-generation contraceptives (RR 1.65, 95% CI 1.20-2.26), and increasing with the dose of ethinyl estradiol (RR 1.42, 1.63, and 2.92 for