Respiratory syncytial virus (RSV) is a major cause of morbidity in infants, young children, and the elderly worldwide. Currently, there is no effective vaccine, and antiviral drugs to control infection are limited. RNA interference is a powerful tool amenable to development of antiviral drugs. Using small interfering RNA (siRNA) targeting the RSV P gene (siRNA-P), RSV replication can be silenced both in vitro and in a BALB/c model of RSV infection. In this study, we examine the effect of siRNA prophylaxis on the primary and memory immune response to RSV infection in mice. We show that mice prophylactically treated with siRNA-P to decrease but not eliminate RSV replication exhibit reduced pulmonary inflammation and lung pathogenesis and produce a robust anti-RSV memory response when subsequently challenged with RSV. The pulmonary T-cell memory response was characterized by high numbers of CD44(hi) CD62L(lo) CD4(+) and CD8(+) T cells, M2 peptide tetramer(+) CD8(+) T cells expressing gamma interferon, and an RSV-specific antibody response. The results support the hypothesis that siRNAs can be developed as effective antiviral drugs that can be used to reduce the viral load and parameters of pathogenesis without limiting the induction of the memory immune response.