Apolipoprotein E (apoE) and clusterin can influence structure, toxicity, and accumulation of the amyloid-β (Aβ) peptide in brain. Both molecules may also be involved in Aβ metabolism prior to its deposition. To assess this possibility, we compared PDAPP transgenic mice that develop age-dependent Aβ accumulation in the absence of apoE or clusterin as well as in the absence of both proteins. apoE^−/− and clusterin^−/− mice accumulated similar Aβ levels but much less fibrillar Aβ. In contrast, apoE^−/−/clusterin^−/− mice had both earlier onset and markedly increased Aβ and amyloid deposition. Both apoE^−/− and apoE^−/−/clusterin^−/− mice had elevated CSF and brain interstitial fluid Aβ, as well as significant differences in the elimination half-life of interstitial fluid Aβ measured by in vivo microdialysis. These findings demonstrate additive effects of apoE and clusterin on influencing Aβ deposition and that apoE plays an important role in regulating extracellular CNS Aβ metabolism independent of Aβ synthesis.