Ease of imaging and abundance of genetic tools make the zebrafish an attractive model host to understand host-pathogen interactions. However, basic knowledge regarding the identity of genes involved in antiviral immune responses is still lagging in this species. We conducted a microarray analysis of the larval zebrafish response to two models of RNA virus infections with very different outcomes. Chikungunya virus (CHIKV) induces a rapid and protective IFN response. Infection with infectious hematopoietic necrosis virus is lethal and is associated with a delayed and inefficient IFN response. A typical signature of IFN-stimulated genes (ISGs) was observed with both viruses, but was stronger for CHIKV. We further compared the zebrafish and human ISG repertoires and made a genomic and phylogenic characterization of the main gene families. We describe a core set of well-induced ISGs conserved across vertebrates, as well as multigenic families diversified independently in each taxon. The conservation of ISGs involved in antiviral signaling indicates conservation of the main feedback loops in these pathways. Whole-mount in situ hybridization of selected transcripts in infected larvae revealed a typical pattern of expression for ISGs in the liver, gut, and blood vessels with both viruses. We further show that some inflammatory genes were additionally induced through IFN-independent pathways by infectious hematopoietic necrosis virus and not by CHIKV. This study provides a useful reference set for the analysis of host-virus interactions in zebrafish and highlights the differences between protective and nonprotective antiviral innate responses.