We examined risk factors for systemic lupus erythematosus (SLE) in 265 recently diagnosed patients in North Carolina and South Carolina and 355 control subjects identified through driver's license records and frequency matched to patients by age, sex, and state. Analyses were limited to exposures before diagnosis (cases) or reference year (control subjects). SLE patients were more likely than control subjects to report a history of allergy to medications (odds ratio [OR] 3.1, 95% confidence interval [CI], 2.1-4.5), particularly to antibiotics. SLE risk increased with history of shingles (OR 2.5, 95% CI 1.1-5.9) and with frequent (more than once per year) cold sores in the 3 years before diagnosis (OR 2.8, 95% CI 1.4-5.4). There was little association with history of mononucleosis, a marker of late infection with Epstein-Barr virus, implanted medical devices, or hepatitis B vaccination. History of lupus in parents or siblings was associated with an increased risk (OR 3.3, 95% CI 1.2-8.6). Further research is needed to clarify whether medication allergies and specific infectious agents are involved in the etiology of SLE. Published by Elsevier Science Inc.