Angiographically documented coronary artery disease (CAD) can progress. Although progression itself is frequently recognized in patients who have undergone repeat cardiac catheterization, its prognostic significance remains unclear. To evaluate the influence of progression on survival, 313 patients with CAD who underwent catheterization twice (39 ± 25 months apart) were followed for 3 to 129 months (mean 41 ± 30) after the second angiogram. At the time of the second angiogram, 21, 91, 113 and 88 patients had 0-, 1-, 2- and 3-vessel CAD, respectively. The mean ejection fraction (EF) of the group was 55 ± 13%. Progression was noted in 139 patients (44%). Of the 313 patients, 33 died and 39 had acute myocardial infarction (AMI) during follow-up. Four-year survival was estimated at 94% and 83% in the nonprogression and progression groups, respectively. Progression was predictive of survival by (univariate) log-rank test (p < 0.01), but only EF (p < 0.001), number of diseased vessels (p < 0.01) and percent stenosis in the left main coronary artery (p < 0.05) were independently significant by (multivariate) Cox regression analysis. Four-year survival without AMI was 89% and 73% in the nonprogression and progression groups, respectively. Progression was related to survival without AMI (p < 0.001) by log-rank test. Cox regression analysis provided 3 independent predictors of survival without AMI: number of diseased vessels (p < 0.01), progression (p < 0.01, relative risk = 2.28) and EF (p < 0.01). Results were similar when analyzing only the 39 AMIs. Thus, for prediction of AMI, progression adds significant information beyond the current status of coronary anatomy and left ventricular function; patients with progressive CAD are at high risk of AMI.