Background. Several genes and their single nucleotide polymorphisms are associated with either spontaneous resolution of hepatitis C infection or better treatment-induced viral clearance. We tested a cohort of intravenous drug users (IVDU) diagnosed with chronic hepatitis C (HCV) for treatment response and its association with the single nucleotide polymorphisms in the Interleukin-6 (rs1800795-IL6) and the Interleukin-28B (rs12979860-IL28B) genes. Methods. The study included 110 Croatian IVDU positive for anti-HCV antibody. Genotyping was performed by PCR based approach. Patients were treated by standard pegylated-interferon/ribavirin and followed throughout a period of four years, during which sustained virological response (SVR) was determined. All data were analysed with statistical package SPSS 19.0 (IBM Corp, Armonk, NY) and PLINK v1.07 software. Results. Patients showed a significantly better response to treatment according to the number of copies of the C allele carried at rs1800795-IL6 (P=0.034). All but one of the patients with CC genotype achieved SVR (93%), whereas the response rate of patients with GG genotype was 64%. The association of rs1800795-IL6 with SVR status remained significant after further adjustment for patients' age, fibrosis staging, and viral genotype (OR 2.15, 95%CI 1.16-4.68, P=0.019). Distributions of allele frequencies at the locus rs12979860-IL28B among the study cohort and the underlying general population were suggestive of a protective effect of CC genotype in acquiring chronic hepatitis C in the Croatian IVDU population. Discussion. The rs1800795-IL6 polymorphism is associated with positive response to treatment in IVDU patients positive for HCV infection. A protective role of rs12979860-IL28B CC genotype in acquiring chronic hepatitis C is