Background. Apolipoprotein E (apoE) is postulated to affect brain A levels through multiple mechanisms - by altering amyloid precursor protein (APP) processing, A degradation, and A clearance. We previously showed that an apoE-derived peptide containing a double repeat of the receptor-binding region was similarly effective in increasing APP processing in vivo. Here, we further examined whether peptides containing tandem repeats of the apoE receptor-binding region (amino acids 141-149) affected APP trafficking, APP processing, and A production. Results. We found that peptides containing a double or triple tandem repeat of the apoE receptor-binding region, LRKLRKRLL, increased cell surface APP and decreased A levels in PS1-overexpressing PS70 cells and in primary neurons. This effect was potentiated by a sequential increase in the number of apoE receptor-binding domain repeats (trimer > dimer > monomer). We previously showed that the apoE dimer increased APP CTF in vivo; to determine whether the dimer also affected secreted APP or A levels, we performed a single hippocampal injection of the apoE dimer in wild-type mice and analyzed its effect on APP processing. We found increased sAPP and decreased A levels at 24 hrs after treatment, suggesting that the apoE dimer may increase -secretase cleavage. Conclusions. These data suggest that small peptides consisting of tandem repeats of the apoE receptor-binding region are sufficient to alter APP trafficking and processing. The potency of these peptides increased with increasing repeats of the receptor binding domain of apoE. In addition, in vivo administration of the apoE peptide (dimer) increased sAPP and decreased A levels in wild-type mice. Overall, these findings contribute to our understanding of the effects of apoE on APP processing and A production both in vitro and in vivo.