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Clinical trials indicate that hormone therapy (HT) does not decrease cardiovascular disease events or angiographic coronary disease progression. The effects of HT on SVG vessels are unknown. To determine whether postmenopausal hormone therapy started after coronary bypass surgery (CABG) decreases saphenous vein graft (SVG) disease, we conducted a multicenter randomized placebo-controlled angiographic study of estradiol+/-medroxyprogesterone started within 6 months of CABG in 83 postmenopausal women. Angiographic and intravascular ultrasound (IVUS) assessment at 6 and 42 months was planned to assess SVG disease progression. The study was stopped early following publication of the Women's Health Initiative Estrogen/Progestin study. Eighty-three subjects underwent a 6-month angiogram with 63 undergoing IVUS. Forty-five subjects completed the 42-month angiogram (20 underwent 42-month IVUS). In analysis of paired 6- and 42-month angiogram and IVUS studies, HT slowed angiographic progression of SVG disease assessed by mean percent stenosis (p<0.001), minimal lumen diameter (p=0.029), and total plaque volume (p=0.006). In contrast, HT accelerated disease progression in non-bypassed native coronary arteries (minimum lumen diameter, p=0.01). SVG disease and closure occurred in 38% subjects within 1-year post-CABG. The groups had similar frequency of cardiovascular events expect for angioplasty that occurred in eight HT compared to one placebo subject (p<0.05). In HT subjects angioplasty was indicated for native coronary arterial stenoses while in the placebo subject angioplasty was indicated for SVG stenosis. This study suggests that hormone treatment may slow SVG disease progression while accelerating atherosclerosis in non-bypassed native coronary arteries.