Respiratory syncytial virus (RSV) infection is the most important viral cause of severe respiratory disease in infants and children worldwide and also forms a serious threat in the elderly. The development of RSV vaccine, however, has been hampered by the disastrous outcome of an earlier trial using an inactivated and parenterally administered RSV vaccine which did not confer protection but rather primed for enhanced disease upon natural infection. Mucosal administration does not seem to prime for enhanced disease, but non-replicating RSV antigen does not induce a strong mucosal immune response. We therefore investigated if mucosal immunization with inactivated RSV supplemented with innate receptor ligands, TLR9 (CpG ODN) and NOD2 (L18-MDP) through the upper or total respiratory tract is an effective and safe approach to induce RSV-specific immunity. Our data show that beta-propiolactone (BPL) inactivated RSV (BPL-RSV) supplemented with CpG ODN and L18-MDP potentiates activation of antigen-presenting cells (APC) in vitro, as demonstrated by NF-κB induction in a model APC cell line. In vivo, BPL-RSV supplemented with CpG ODN/L18-MDP ligands induces local IgA responses and augments Th1-signature IgG2a subtype responses after total respiratory tract (TRT), but less efficient after upper respiratory tract (intranasal, IN) immunization. Addition of TLR9/NOD2 ligands to the inactivated RSV also promoted affinity maturation of RSV-specific IgG antibodies and shifted T cell responses from mainly IL-5-secreting cells to predominantly IFN-γ-producing cells, indicating a Th1-skewed response. This effect was seen for both IN and TRT immunization. Finally, BPL-RSV supplemented with TLR9/NOD2 ligands significantly improved the protection efficacy against a challenge with infectious virus, without stimulating enhanced disease as evidenced by lack of eotaxin mRNA expression and eosinophil infiltration in the lung. We conclude that mucosal immunization with inactivated RSV antigen supplemented with TLR9/NOD2 ligands is a promising approach to induce effective RSV-specific immunity without priming for enhanced disease.