Herein, we investigated the risk of juvenile-onset systemic lupus erythematosus (JSLE) in children with atopic dermatitis (AD). From 2000 to 2007, 192,357 children with newly diagnosed AD and 769,428 matched non-AD controls were identified. By the end of 2008, incidences and hazard ratios (HRs) of JSLE were measured. JSLE incidence in the AD cohort was 2.90-fold greater than that in the non-AD cohort (3.25 vs. 1.12 per 100,000 person-years), with a Cox model-measured adjusted HR of 2.92 (95% CI: 1.85-4.60); the risk of JSLE was greater for older children and girls. The AD-to-non-AD cohort HR was 6.6 (95% CI: 2.88-13.1) for children aged >12 years compared with 1.81 (95% CI: 0.98-3.32) for children aged ≤ 12 years. The HR of JSLE in AD children increased from 1.55 (95% CI: 0.88-2.76) for those with ≤ 3 clinical visits to 66.3 (95% CI: 33.1-132.8) for those with >6 visits (p < 0.0001, by trend test). The risk of developing SLE in the AD cohort was the highest within five years after AD diagnosis (HR: 4.02; 95% CI: 2.83-7.08). Children with AD are at a high risk of developing JSLE during their growth period.