Background: Two major drawbacks of current subcutaneous specific immunotherapy are the risk to induce severe anaphylactic reactions and the need of multiple injections of the allergen to reduce IgE-mediated hypersensitivity. The sustained release of allergens over time provided by poly(lactide-co-glycolide) microparticles (MP) could mimic the current therapeutic schedule and decrease their allergenicity. Moreover, MP could also co-deliver Th1 immunoadjuvants, such as CpG motifs. Methods: Ovalbumin (OVA)-sensitized BALB/c mice were treated intradermally with OVA or OVA plus CpG containing MP. OVA-specific IgG1 and IgG2a as well as IgE total levels and cytokine production were assessed throughout the experiment. The protection exerted by the MP against allergen challenge was estimated with body temperature changes, mortality and other symptoms. Results: Microparticulated treatments, irrespective of the presence of CpG motifs, elicited a lower IgE/IgG2a ratio than those induced by the allergen in solution (free or with adjuvants). However, after induction of the anaphylactic shock, only mice treated with MP co-encapsulating OVA plus CpG showed a significant lower decrease in body temperature and were totally protected from death. Mice that were injected with OVA plus CpG in solution or with Alum displayed a marked fall of temperature accompanied by high mortality rates (70–100%). Conclusion: MP encapsulating both OVA, as an allergen model, and CpG sequences, as a pro-Th1 adjuvant, decreased the risk for OVA sensitization (IgE induction) and protected sensitized mice from anaphylactic shock after allergen provocation. Therefore, the combination of allergens and CpG sequences into MP could perform a safer alternative to current specific immunotherapy.