In-vivo studies were carried out to investigate the protective effect of a synthetic viral analogue (poly I:C) against Ostreid herpes virus (OsHV-1 mu var). Pacific oysters (Crassostrea gigas) were immune-primed by intramuscular injection of 240 mu g of poly I:C or sterile seawater at 1 day prior to infection with OsHV-1 mu var. Poly I:C injection induced an antiviral state in C gigas as the percentage of viral-infected oysters at 48 h post infection was significantly lower in the poly I:C treatment (11%) compared to seawater controls (100%). In an additional experiment, we demonstrated that the protective role of poly I:C is reproducible and elicits a specific antiviral response as immune-priming with heat-killed Vibrio splendidus provided no protection against subsequent viral infection. In both experiments, genes homologous to a toll-like receptor (TLR), MyD88, interferon regulatory factor (IRF) and protein kinase R (PKR) were up-regulated in oysters immune-primed with poly I:C compared to seawater controls (p < 0.05). The MyD88, IRF and PKR genes were also significantly up-regulated in response to OsHV-1 mu var infection (p < 0.05), which is suggestive that they are implicated in the antiviral response of C gigas. Our results demonstrate that C gigas can recognise double-strand RNA to initiate an innate immune response that inhibits viral infection. The observed response has striking similarities to the hallmarks of the type-1 interferon response of vertebrates.