Previous studies in the authors' laboratory have demonstrated that degradation of arterial elastin produces vessel dilatation, decreased vessel distensibility, and vessel elongation which can cause tortuosity. By contrast, degradation of collagen produces increased vessel distensibility and rupture. However, neither degradation of elastin nor of collagen produced the true gross enlargement characteristic of human aneurysms. The present study was performed to identify the connective tissue critical to aneurysm formation. Vessel dimensions were measured repeatedly in human arteries during progressive enzymatic degradation. Experiments were performed on six intact human common, external and internal iliac arteries, and two aneurysmal human common iliac arteries. The vessels were mounted in vitro and subjected to pressure steps up to 200 mmHg while diameters were measured. Repeated pressure-diameter curves were obtained for up to 18 h during treatment with elastase or collagenase. Degradation of elastin produced moderate dilatation (6-10% at 100 mmHg) with decreased vessel distensibility; this occurred as the load was shifted to remaining collagen. Degradation of collagen produced greater dilatation (10-23% at 100 mmHg), increased distensibility, and vessel rupture. These findings suggest that the critical element in both the gross enlargement and rupture of aneurysms resides in collagen. They also suggest that, in vessels obtained from patients with a family history of aneurysms, defects should be sought in: (i) the structure of collagen; (ii) increased susceptibility of collagen to degradation by endogenous mechanisms; (iii) increased endogenous collagenolytic activity; or (iv) decreased inhibition of endogenous collagenolytic activities.