Cerebral amyloid angiopathy (CAA) is a common neuropathological finding and is characterized by deposition of fibrillar amyloid in cortical and leptomeningeal vessels. In this study we describe the macroscopic and microscopic neuropathological findings of 5 patients with severe CAA-associated secondary vascular changes, including smooth muscle cell degeneration, hyalinization, ‘double-barreling’ phenomenon, macrophage infiltration, and aneurysmal dilatation of the vessel wall. In 3 of the 5 patients these vascular changes were associated with multiple small hemorrhages, whereas in 2 patients areas of ischemic necrosis were observed. However, none of these patients suffered from large (lobar) hemorrhagic accidents. Nevertheless, severe CAA, particularly when associated with secondary vascular pathology, may lead to vascular dementia-like ischemic changes. Hence, the distinction between patients with severe CAA and secondary vascular abnormalities from those suffering from vascular dementia can be difficult. We speculate that CAA, particularly when associated with secondary vascular pathology, although not resulting in large hemorrhages, may contribute to cognitive decline. The functional impact of CAA and CAA-related secondary vascular changes on cognitive performance warrants further exploration.