Background: There is concern that exogenous female hormones may worsen disease activity in women with systemic lupus erythematosus (SLE). Objective: To evaluate the effect of hormone replacement therapy (HRT) on disease activity in postmenopausal women with SLE. Design: Randomized, double-blind, placebo-controlled noninferiority trial conducted from March 1996 to June 2002. Setting: 16 university-affiliated rheumatology clinics or practices in 11 U.S. states. Patients: 351 menopausal patients (mean age, 50 years) with inactive (81.5%) or stable-active (18.5%) SLE, Interventions: 12 months of treatment with active drug (0.625 mg of conjugated estrogen daily, plus 5 mg of medroxyprogesterone for 12 days per month) or placebo. The 12-month follow-up rate was 82% for the HRT group and 87% for the placebo group. Measurements: The primary end point was occurrence of a severe flare as defined by Safety of Estrogens in Lupus Erythematosus, National Assessment-Systemic Lupus Erythematosus Disease Activity Index composite, Results: Severe flare was rare in both treatment groups: The 12-month severe flare rate was 0.081 for the HRT group and 0.049 for the placebo group, yielding an estimated difference of 0.033 (P = 0.23). The upper limit of the 1-sided 95% CI for the treatment difference was 0.078, within the prespecified margin of 9% for noninferiority. Mild to moderate flares were significantly increased in the HRT group: 1.14 flares/person-year for HRT and 0.86 flare/person-year for placebo (relative risk, 1.34; P = 0.01). The probability of any type of flare by 12 months was 0.64 for the HRT group and 0.51 for the placebo group (P = 0.01). In the HRT group, there were 1 death, 1 stroke, 2 cases of deep venous thrombosis, and 1 case of thrombosis in an arteriovenous graft; in the placebo group, 1 patient developed deep venous thrombosis. Limitations: Findings are not generalizable to women with high-titer anticardiolipin antibodies, lupus anticoagulant, or previous thrombosis. Conclusions: Adding a short course of HRT is associated with a small risk for increasing the natural flare rate of lupus. Most of these flares are mild to moderate. The benefits of HRT can be balanced against the risk for flare because HRT did not significantly increase the risk for severe flare compared with placebo. © 2005 American College of Physicians.