Cytotoxic T lymphocytes (CTLs) play an important role in the immune response against respiratory syncytial virus (RSV) infection. The cell surface molecule lymphocyte function-associated antigen 1 (LFA-1) is an important contributor to CTL activation, CTL-mediated direct cell lysis, and lymphocyte migration. In an attempt to determine the role of LFA-1 during RSV infection, we treated BALB/c mice with monoclonal antibodies to LFA-1 at days −1, +1, and +4 relative to primary RSV infection. Anti-LFA-1 treatment during primary RSV infection led to reduced illness and delayed clearance of virus-infected cells. CTLs from RSV-infected mice that were treated with anti-LFA-1 exhibited diminished cytolytic activity and reduced gamma interferon production. In addition, studies with BrdU (5-bromo-2′-deoxyuridine)- and CFSE [5-(and 6)-carboxyfluorescein diacetate succinimidyl ester]-labeled lymphocytes showed that anti-LFA-1 treatment led to delayed proliferation during RSV infection. These results indicate that LFA-1 plays a critical role in the initiation of the immune response to RSV infection by facilitating CTL activation. These results may prove useful in the development of new therapies to combat RSV infection or other inflammatory diseases.