Atherosclerosis begins in the teenage years and progresses over time in susceptible individuals. It is unknown, however, whether coronary angiography in middle-aged adults showing no evidence of atherosclerosis identifies individuals at low risk for subsequent development of coronary artery disease (CAD). We identified 4068 patients ≥40 years of age who had at least two coronary angiograms between January 1, 1990 and March 31, 2011. Of these, 227 patients (5.8%) had no CAD and 251 patients (6.4%) had mild atherosclerotic disease (stenosis <30%) on the initial angiogram. Patients in the normal-angiogram group were younger, more often female, and less likely to use tobacco than patients in the mild-atherosclerosis group, while rates of diabetes and hypertension were the same. Angiographic evidence of any CAD and obstructive CAD was apparent in 26% and 4.8%, respectively of the normal-angiogram group on subsequent angiography performed 75 ± 46 months later. Myocardial infarction and revascularization occurred in 4.8% and 3.5%, respectively. Progression of CAD (odds ratio = 10.2), development of obstructive CAD (odds ratio = 8.9), myocardial infarction (odds ratio = 2.7), and revascularization (odds ratio = 8.4) were more frequent in the mild-atherosclerosis group. In summary, 26% of middle-aged adults with a normal coronary angiogram who had subsequent angiography for clinical reasons developed CAD, although the annual rates of myocardial infarction or revascularization were very low. Even mild atherosclerosis on the initial angiogram increased the rate of progression of CAD by 10-fold and the rate of revascularization by 8-fold.