Pulmonary surfactant protein D (SP-D), which is a member of the collectin family, is implicated in pulmonary defense against pathogens. To determine whether SP-D is involved in first-line immunity against Candida albicans, an important respiratory fungus, the interaction of SP-D with C. albicans was studied. SP-D was found to bind C. albicans, resulting in agglutination of the microorganisms. Binding was calcium dependent and was inhibited by competing sugars maltose or mannose. Incubation of C. albicans with SP-D resulted in profound fungal growth inhibition and decreased hyphal outgrowth. Furthermore, it was found that SP-D inhibited phagocytosis of C. albicans by alveolar macrophages. These data suggest that the lung collectin SP-D has an important role in first-line defense against C. albicans in the lung, by agglutinating C. albicans and limiting their growth, without the need for macrophage activation.