The pulmonary collectin, lung surfactant protein D (SP‐D), plays a role in host defense mediated by the interaction of surface carbohydrates of inhaled pathogens with the lectin domains of SP‐D. Respiratory syncytial virus (RSV), the most important viral pathogen of neonates and infants, encodes a highly glycosylated attachment protein, G. Binding studies were performed with G protein from RSV (human, A2 strain) and both native and recombinant human SP‐D. The effect of recombinant trimeric SP‐D lectin domains (rSP‐D) on the interaction between RSV and host cells was determined by two methods: an infectivity study with monolayers of Hep‐2C cells and in vivo infections in BALB / c mice. These studies show that full‐length and recombinant SP‐D bind to RSV G protein in a concentration‐dependent manner. Both EDTA and mannan inhibited binding of full‐length SP‐D. These results indicate that binding occurs via the carbohydrate recognition domain of the SP‐D. The recombinant SP‐D inhibited RSV infectivity in cell culture in a dose‐dependent manner, giving 100 % inhibition of replication. Intranasal administration of recombinant SP‐D to RSV‐infected mice inhibited replication of the virus in the lungs, reducing levels of lung virus by 80 %. These results suggest that SP‐D plays a major role in clearing RSV from the lungs.