Little is known about the identities and roles of antigen-presenting cells upon exposure to antigens of respiratory syncytial virus (RSV). Here, we focused on elucidating the importance of alveolar macrophages in conferring protective immunity in mice administered a liposome-encapsulated recombinant fragment of the RSV G protein. Mice were depleted of alveolar macrophages by intranasal inoculation of liposome-encapsulated dichloromethylenediphosphonic acid (DMDP). Mice depleted of alveolar macrophages prior to immunization developed reduced levels of serum RSV-neutralizing antibody and showed dramatically impaired protection against RSV challenge. The severity of interstitial inflammation was also markedly reduced in macrophage-depleted mice. In conclusion, this study demonstrates a pivotal role for alveolar macrophages during exposure to liposome-encapsulated RSV antigen in initiating both protective and histopathological responses against RSV.