© 2014 by The North American Menopause Society. Objective This study aims to present methods and baseline data from the Early versus Late Intervention Trial with Estradiol (ELITE), the only clinical trial designed to specifically test the timing hypothesis of postmenopausal hormone therapy (HT). The timing hypothesis posits that HT effects depend on the temporal initiation of HT relative to time since menopause. Methods ELITE is a randomized, double-blind, placebo-controlled trial with a 2 × 2 factorial design. Six hundred forty-three healthy postmenopausal women without cardiovascular disease were randomized to oral estradiol or placebo for up to 6 to 7 years according to time since menopause (<6 or ≥10 y). Carotid artery intima-media thickness (CIMT) and cardiac computed tomography were conducted to determine HT effects on subclinical atherosclerosis across menopause strata. Results Participants in the early and late postmenopausal strata were well-separated by mean age (55.4 vs 65.4 y) and median time since menopause (3.5 vs 14.3 y). Expected risk factors (age, blood pressure, and body mass index) were associated with CIMT at baseline in both strata. In the early postmenopausal group, but not in the late postmenopausal group, we observed significant associations between CIMT and factors that may play a role in the responsiveness of atherosclerosis progression according to timing of HT initiation. These include low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, sex hormone-binding globulin, and serum total estradiol. Conclusions The ELITE randomized controlled trial is timely and unique. Baseline data indicate that ELITE is well-positioned to test the HT timing hypothesis in relation to atherosclerosis progression and coronary artery disease.