Interferon induced proteins with tetratricopeptide repeats (IFITs) are RNA binding effectors that restrict infection by diverse RNA viruses. Among the IFIT family, how IFIT3 recognizes RNA remains the least understood. Here, we identify IFIT3 as preferentially associating with N6 methyladenosine m6A-modified hepatitis C virus (HCV) genomic RNA and host transcripts to restrict HCV infection. IFIT3 cellular RNA binding sites and m6A sites, mapped transcriptome wide by HyperTRIBE seq during HCV infection, showed significant overlap. This m6A preference was further supported by findings that IFIT3 binding sites significantly overlapped those of established m6A binding proteins; that inhibiting m6A installation reduced IFIT3 association with m6A modified HCV RNA and cellular transcripts; that IFIT3 co purified more efficiently with m6A modified short RNA probes than with unmodified controls; and that mutating m6A consensus motifs in the HCV genome reduced IFIT3 association with viral RNA. Structure-function analyses identified two regions required for RNA probe binding: tetratricopeptide repeat domains 1-2 (TPR1-2) and a previously uncharacterized predicted helical hairpin between TPRs 6 and 7. In infected cells, the helical hairpin was required for IFIT3 association with HCV RNA but dispensable for interactions with other IFIT proteins. Conversely, TPR1-2 was dispensable for HCV RNA binding but essential for IFIT2 interaction, establishing that these functions are structurally separable. Loss of either region diminished antiviral activity, as indicated by increased levels of HCV RNA in clarified supernatants. Consistent with models of m6A linked restriction of late stages of infection, extracellular HCV RNA showed reduced m6A and decreased IFIT3 association relative to intr