Objective: The aim of this study was to assess the relationship of the timing of hormone therapy (HT) use with angiographic coronary artery disease (CAD) and cardiovascular disease (CVD) events in women with natural versus surgical menopause. Methods: We studied 654 postmenopausal women undergoing coronary angiography for the evaluation of suspected ischemia. Timing and type of menopause, HT use, and quantitative angiographic evaluations were obtained at baseline, and the women were followed for a median of 6 years for CVD events. Results: Ever users of HT had a significantly lower prevalence of obstructive CAD compared with never users (age-adjusted odds ratio, 0.41 [0.28-0.60]). Women with natural menopause initiating HT before age 55 years had lower CAD severity compared with never users (age-adjusted β [SE] =-6.23 [1.50], P < 0.0001), whereas those initiating HT at age 55 years or more did not differ statistically from never users (-3.34 [2.13], P = 0.12). HT use remained a significant predictor of obstructive CAD when adjusted for a "healthy user" model (odds ratio, 0.44 [0.30-0.73]; P = 0.002). An association between HT and fewer CVD events was observed only in the natural menopause group (hazard ratio [95% CI], 0.60 [0.41-0.88]; P = 0.009) but became nonsignificant when adjusted for the presence or severity of obstructive CAD. Conclusions: Using the quantitative measurements of the timing and type of menopause and HT use, earlier initiation of HT was associated with less angiographic CAD in women with natural but not surgical menopause. Our data suggest that the effect of HT use on reduced cardiovascular event rates is mediated by the presence or absence of angiographic obstructive atherosclerosis. © 2011 by The North American Menopause Society.