Although allergen immunotherapy is basically a story of success, it still needs improvement. The goal of this study was to optimize parenteral and oral allergen formulations through using the biocompatible polymer of lactic and glycolic acid (PLGA). Subcutaneous application of birch pollen allergen Bet v 1 encapsulated in nanoparticles biased the immune response toward Th1 in allergic mice and did not elicit granuloma formation in mice and in human volunteers. When oral immunotherapy of mice was tried with birch pollen–filled PLGA microparticles, mucosal targeting was indispensable for achieving any immune response, and targeting of M-cells was necessary for modulating an ongoing allergic response toward Th1. The authors suggest that biocompatible PLGA nano- or microparticles can be useful tools for upgrading therapy of type I allergy.