Our recent data demonstrates a critical role of the RIG-I-like receptor (RLR) family in regulating antifungal immunity against Aspergillus fumigatus in a murine model. However, the importance of this pathway in humans and the cell type(s) which utilize this innate immune receptor to detect A. fumigatus remains unresolved. Here using patients who underwent hematopoietic stem cell transplantation (HSCT), we demonstrate that a polymorphism in human MAVS present in the donor genome was associated with the incidence of invasive pulmonary aspergillosis (IPA). Moreover, in a separate cohort of confirmed IPA patients, polymorphisms in the IFIH1 gene alter the inflammatory response, including interferon-responsive chemokines. Returning to our murine model, we now demonstrate that CD11c + SiglecF + alveolar macrophages require Mavs expression to maintain host resistance against A. fumigatus . Our data support the role of MAVS signaling in mediating antifungal immunity in both mice and human at least in part through the role of MAVS-dependent signaling in alveolar macrophages.