Cerebral capillary sequestration and blood‐brain barrier (BBB) permeability to apolipoproteins E2 (apoE2), E3 (apoE3), and E4 (apoE4) and to their complexes with sAβ_1–40, a peptide homologous to the major form of soluble Alzheimer's amyloid β, were studied in perfused guinea pig brain. Cerebrovascular uptake of three apoE isoforms was low, their blood‐to‐brain transport undetectable, but uptake by the choroid plexus significant. Binding of all three isoforms to sAβ_1–40 in vitro was similar with a K_D between 11.8 and 12.9 nM. Transport into brain parenchyma and sequestration by BBB and choroid plexus were negligible for sAβ_1–40‐apoE2 and sAβ_1–40‐apoE3, but significant for sAβ_1–40‐apoE4. After 10 min, 85% of sAβ_1–40‐apoE4 taken up at the BBB remained as intact complex, whereas free sAβ_1–40 was 51% degraded. Circulating apoE isoforms have contrasting effects on cerebral capillary uptake of and BBB permeability of sAβ. ApoE2 and apoE3 completely prevent cerebral capillary sequestration and blood‐to‐brain transport of sAβ_1–40. Conversely, apoE4, by entering brain microvessels and parenchyma as a stable complex with sAβ, reduces peptide degradation and may predispose to cerebrovascular and possibly enhance parenchymal amyloid formation under pathological conditions.