Collectins are multimeric host defense lectins with trimeric carbohydrate recognition domains (CRDs) and collagen and N-terminal domains that form higher order structures composed of four or more trimers. Recombinant trimers composed of only the CRD and adjacent neck domain (NCRD) retain binding activity for some ligands and mediate some functional activities. The lung collectin surfactant protein D (SP-D) has strong neutralizing activity for influenza A viruses (IAV) in vitro and in vivo, however, the NCRD derived from SP-D has weak viral binding ability and lacks neutralizing activity. Using a panel of monoclonal antibodies (mAbs) directed against the NCRD we show that mAbs binding near the lectin site inhibit antiviral activity of full length SP-D, but mAbs which bind other sites on the CRD do not. Two of the non-blocking mAbs significantly increased binding and antiviral activity of NCRDs as assessed by hemagglutination and neuraminidase inhibition and by viral neutralization. mAb mediated cross-linking also enabled NCRDs to induce viral aggregation and to increase viral uptake by neutrophils and virus-induced respiratory burst responses by these cells. These results show that antiviral activities of SP-D can be reproduced without the N-terminal and collagen and that cross-linking of NCRDs is essential for antiviral activity of SP-D with respect to IAV.