The feasibility of employing a vaccine composed of the purified fraction 21 of Quillaja saponaria (QS-21) and the fusion (F) protein of respiratory syncytial virus (RSV) to induce protective immune responses in the lower respiratory tract of Balb/c mice was examined. Our goal was to compare local and systemic immune responses with those induced following immunization with the protein adsorbed to aluminium hydroxide (F/ALOH) adjuvant or by experimental infection. Sera from mice vaccinated with the QS-21 formulation (F/QS-21) contained elevated anti-F protein IgG antibody titres that were dependent on the dose of QS-21 employed. Similar to the immune responses generated by experimental infection, the sera from mice vaccinated with F/QS-21 possessed greater capacity to neutralize virus infectivity that was associated with the generation of heightened complement-fixing IgG2a antibody titres. In contrast, vaccination with F/ALOH elicited systemic immune responses that were characterized by a predominance of protein-specific antibodies of the IgG1 subclass and lower neutralizing antibody titres. The capacity of F/QS-21 to facilitate local pulmonary immune responses was also examined and found to be similar to those induced by experimental infection. After virus challenge, a 90-fold increase in the number of F protein-specific antibody-secreting cells was observed and associated with the clearance of virus from the infected lungs. Moreover, elevated levels of antigen-dependent killer cell activity were detected and appeared to be mediated by class I major histocompatibility complex restricted CD8+ T cells. Additional characterization of the pulmonary immune response was performed on the cellular infiltrates obtained after bronchoalveolar lavage and on formalin-fixed lung tissue. The local protective immune responses induced after challenge of the groups immunized with F/QS-21 or infectious virus were significantly different from those elicited in naive control mice injected with adjuvant alone, or in mice immunized with F/ALOH. The cellularity of the lavage fluids from the former groups was characterized by a significantly greater percentage of lymphocytes and less neutrophils. In similar fashion histological evaluation of the lungs from mice immunized with F/QS-21 or infectious virus revealed significantly elevated local immune responses after challenge. In conclusion, the results suggest that formulation with F/QS-21 alters the qualitative and quantitative nature of the immune response to the F glycoprotein when compared with the traditional aluminium-based adjuvants.