Detection of respiratory syncytial virus (RSV) in blood, including mononuclear leukocytes and organs other than the lung, suggests that RSV disseminates outside the respiratory tract. In this study, the role of platelets in host defense against RSV was explored using an in vitro model. Platelets, also produced in the lungs, are increasingly recognized as an important part of host immune responses and may therefore play a role in modulating lung infections and clearing RSV viremia. In human peripheral blood mononuclear cells (PBMCs), platelets significantly reduced RSV infection of monocytes, monocyte activation, and interferon (IFN)α/γ production. Direct contact of platelets with PBMCs modulated the immune response when stimulated with Poly I:C (TLR3) and R848 (TLR7/8), Toll-like receptors (TLRs) involved in the recognition of RSV, and led to an enhanced IFNα/γ production. This suggested that reduction in RSV infection of monocytes in the presence of platelets could be IFN dependent; blocking IFNα receptor 2 (IFNAR2) on PBMCs indeed increased RSV infection. In addition, IFNs were not detected when PBMCs were stimulated with inactivated RSV, indicating that infection of monocytes was important for the induction of IFN responses and that the platelet-mediated reduced RSV infection was responsible for the decreased IFN levels. Furthermore, platelets could internalize RSV reducing the amount of viral particles that could infect monocytes. Our findings suggest that platelets may play a role in the clearance of RSV viremia by internalizing viral particles and by enhancing type I IFN production from PBMCs, which subsequently exert antiviral effect on host cells.