Here we evaluated the suitability of the synthetic adjuvant IC31® to potentiate the protective capacity of PD5 protein (domain III of the envelope protein of dengue 2 virus fused to the carrier protein P64k). Unlike Alum, PD5 mixed with IC31® induced complete protection against virus challenge in mice and increased IFN-γ secretion after in vitro re-stimulation. The induced antibody response was highly specific to the homologous serotype and showed both IgG1 and IgG2a subtypes. IC31® is a promising adjuvant for PD5 recombinant protein based vaccination against dengue. Future work should address the suitability of PD5/IC31® formulations in non-human primate models.