Human apolipoprotein (ApoE) genotype influences the development of Alzheimer's disease and cerebral amyloid angiopathy (CAA). Specific mutations within the amyloid-β protein (Aβ) peptide have been identified that cause familial forms of CAA. However, the effect of APOE genotype on accumulation of CAA mutant Aβ in brain is not well understood. In the present study, we determined how human ApoE3 or ApoE4 influence cerebral Aβ accumulation in transgenic mice (Tg-SwDI) that accumulate human Dutch/Iowa (E22Q/D23N) CAA mutant Aβ in brain, primarily in the form of fibrillar cerebral microvascular amyloid. Using Tg-SwDI mice bred onto a human APOE3/3 or human APOE4/4 background, we found that both human ApoE3 and ApoE4 proteins led to a strong reduction in the amount of cerebral microvascular amyloid with an unexpected concomitant appearance of extensive fibrillar parenchymal plaque amyloid. There was strong colocalization of all ApoE proteins with fibrillar amyloid deposits in the mice. In Tg-SwDI/hAPOE3/3 and Tg-SwDI/hAPOE4/4 mice, there was no change in the levels of total Aβ₄₀ and Aβ₄₂ or in the amounts of soluble and insoluble Aβ in brain compared with Tg-SwDI mice on the endogenous mouse APOE background. The shift from primarily cerebral microvascular amyloid to parenchymal plaque amyloid in Tg-SwDI/hAPOE3/3 and Tg-SwDI/hAPOE4/4 mice resulted in a parallel shift in the association of activated microglia. These findings indicate that human ApoE has a strong influence on the spatial development of human Dutch/Iowa CAA mutant amyloid accumulation in mouse brain and that microglial activation is in response to the spatial accumulation of fibrillar amyloid.