Multiple host factors are known to play important roles in hepatitis C virus (HCV) replication, in immune responses induced by HCV infection, or in processes that facilitate virus escape from immune clearance, while yet only few studies examined the contribution of long non-coding RNAs (lncRNAs/lncRs). Using microarrays, we identified lncRNAs with altered expression levels in HCV replicating Huh-7.5 hepatoma cells. Of these, lncR 8(/) was confirmed by quantitative real-time PCR (qRT-PCR) to be upregulated early after HCV infection. After suppressing the expression of lncR 8, HCV RNA and protein were downregulated, confirming a positive correlation between lncR 8 expression and HCV replication. lncR 8 knockdown in Huh-7.5 cells reduced expression of the neighboring gene G protein-coupled receptor 55 () mRNA level at early times, and leads to increased levels of several Interferon stimulated genes (ISGs) including , and . Importantly, the effect of lncR 8 on ISGs and precedes its effect on HCV replication. Furthermore, knockdown of mRNA induces ISG expression, providing a possible link between lncR 8 and ISGs. We conclude that HCV induces lncR 8 expression, while lncR 8 indirectly favors HCV replication by stimulating expression of its neighboring gene , which in turn downregulates expression of ISGs. The latter fact is also consistent with an anti-inflammatory role of . These events may contribute to the failure to eliminate ongoing HCV infection.