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Abstract Purpose  Brain-derived neurotrophic factor (BDNF) plays an important role in neuroprotection and repair, but long-term delivery from polymer systems has been challenging. We investigated the role the chemistry of the polymer played in loading and delivery of BDNF via microspheres, which are suitable for minimally invasive administration. Methods  We synthesized polymers based on PLGA and PEG to determine what components augmented loading and delivery. We characterized microspheres fabricated from these polymers using a battery of tests, including sizing, in vitro release, and bioactivity of the BDNF using PC12 cells engineered to express the trkB receptor. Results  We found that a triblock polymer of PLGA, PLL, and PEG led to the delivery of BDNF for periods of time greater than 60 days and that the BDNF delivered was bioactive. The microsphere size was amendable to injection via a 30 gauge needle, allowing minimally invasive delivery. Conclusions  PLGA-PLL-PEG leads to greater loading and longer-term delivery of BDNF than PLGA or a blend of the polymers. We hypothesize that the introduction of an amphiphilic PLGA-based polymer increases the interaction of the BDNF with the polymer and leads to release that more closely correlates with the degradation of the polymer. [ABSTRACT FROM AUTHOR]