Natural IFN-producing cells (NIPC), also called plasmacytoid dendritic cells, represent an essential component of the innate immune defense against infection. Despite this, not much is known about the pathways involved in their activation by non-enveloped viruses. The present study demonstrates that the non-enveloped foot-and-mouth disease virus (FMDV) cannot stimulate IFN-alpha responses in NIPC, unless complexed with FMDV-specific immunoglobulins. Stimulation of NIPC with such immune complexes employs FcgammaRII ligation, leading to strong secretion of IFN-alpha. In contrast to the stimulation of NIPC by many enveloped viruses, FMDV induction of IFN-alpha production requires live virus. It is necessary for the virus to initiate its replicative cycle. Moreover, it is an abortive replication, as witnessed by the decrease of dsRNA levels and viral titers with time post infection. Sensitivity of the NIPC stimulation to wortmannin and chloroquin, but not leupeptin, indicates an essential role for the pre-lysosomal stage endosomal compartment. In conclusion, the present study demonstrates that immune complexes provide the means for a non-interferogenic virus to induce IFN-alpha responses by NIPC. This indicates an important link between NIPC and antibodies in immune responses against non-enveloped viruses such as FMDV.