Prophylactic vaccination of cancer patients and recipients of hematopoietic stem cell transplant is generally a simple, efficient and cost-effective manner by which to prevent unnecessary infection and enhance overall clinical outcomes. However, some neoplastic conditions, particularly B-cell malignancies, impart a degree of immunosuppression that complicates traditional prophylactic approaches. Here, we make the case that the application of dendritic cell (DC) immunotherapy for the prophylaxis of infectious disease is both appropriate and cost effective for certain niche populations who are at risk of increased morbidity and who respond poorly to traditional vaccination, particularly influenza vaccination. Here we review the full spectrum of our preclinical work in this area, results demonstrating that DCs loaded with subunit recombinant hemagglutinin can generate robust hemagglutinin-specific immune responses both in vitro and in vivo. In vivo data indicated that a single injection of hemagglutinin-loaded DC was sufficient to generate high-titer antibody responses that could mediate protective immunity to lethal influenza virus challenge. The results suggest that DC immunotherapy for influenza prophylaxis is safe and feasible and that clinical studies might be warranted.