Both cerebral amyloid angiopathy and Alzheimer's disease pathology involve abnormal β-amyloid processing. We aim to elucidate the relationship of the apolipoprotein E (APOE) genotypes with amyloid angiopathy in the presence of variable amounts of Alzheimer's pathology. Data came from 1062 autopsied subjects from 2 community-based studies of aging. Common neuropathologies including Alzheimer's disease and amyloid angiopathy were assessed using uniform methods. APOE was genotyped by sequencing the 2 polymorphisms in codons 112 and 158 of exon 4. We examined the associations of APOE with amyloid angiopathy using ordinal logistic regression analyses, controlling for demographics and subsequently Alzheimer's and other common pathologies. Moderate to severe amyloid angiopathy was identified in 35.2% (n = 374) of the subjects; 15.3% (n = 162) of the subjects were APOE ε2 carriers; and 26.1% (n = 277) ε4 carriers. Adjusting for demographics, the presence of ε4 allele, but not ε2, was associated with more severe amyloid angiopathy. After further adjustment for Alzheimer's pathology, both ε2 (odds ratio 1.707, 95% confidence interval 1.236-2.358, p = 0.001) and ε4 (odds ratio 2.284, 95% confidence interval 1.730-3.014, p < 0.001) were independently associated with amyloid angiopathy. The results were confirmed by path analysis. Furthermore, APOE ε4 carriers, but not ε2 carriers, were more likely to have capillary amyloid angiopathy. Accounting for capillary involvement did not alter the APOE associations with amyloid angiopathy. We conclude that both APOE ε2 and ε4 alleles are associated with more severe cerebral amyloid angiopathy, and the direct effect of ε2 is masked by the allele's negative association with comorbid Alzheimer's pathology. APOE ε4, but not ε2, is associated with capillary amyloid angiopathy.