Fibulin-4 is not only involved in connective tissue development and elastic fiber formation, but also plays critical neoplastic roles in tumor growth by activating Wnt/β-Catenin signaling in human. Recently, Fibulin-4 was shown to associate with grass carp reovirus (GCRV) outer capsid proteins and might relate to viral hemorrhagic disease in grass carp Ctenopharyngodon idella. Here, we monitored the expression pattern of Fibulin-4 during the infection course of GCRV at both translational and transcriptional levels, and found that Fibulin-4 was significantly suppressed upon the viral challenge in grass cap GCO cells. Over expression of Fibulin-4 was achieved by transduction of pEGFP-Fibulin-4 plasmids into GCO cells, which was confirmed by both Western blot and Real time RT-PCR analysis. In GCO cells with over-expression of Fibulin-4, significantly increase of viral protein synthesis and progeny virus production was detected. Our study indicated that Fibulin-4 displayed pro-viral function and was inhibited during viral challenge. Thus, repression of Fibulin-4 expression seemed to be involved in anti-viral response in grass carp Ctenopharyngodon idella.