Background: Specific single nucleotide polymorphisms (SNPs) near the interferon lambda-3 (IFNλ3) gene (formerly interleukin 28B) influence the response to treatment with interferon in hepatitis C patients. We aimed to investigate such an influence in hepatitis D patients. Methods: The study population consisted of hepatitis D patients who were previously treated with pegylated interferon for one year and who were spontaneous clearers of the virus post recent superinfection. The SNP of IFNλ3, rs12979860, was determined by polymerase chain reaction-restriction fragment length polymorphism protocol. Results: The total number of patients was 64; median age was 30.5 years and 53 were male. The number of patients with sustained virological response 1 year post-treatment was 17, non-responders 29, relapsers 11 and spontaneous clearers post superinfection 7. Cirrhosis was present in 28 (44%). IFNλ3, rs12979860 genotype CC, was present in 41 (64.1%), CT in 21 (32.8%) and TT in 2 (3.1%). There was no difference in the body mass index, baseline alanine aminotransferase, hepatitis B e antigen and HBV DNA status among patients with sustained response and response failure (no response or relapse). The median age of response failures was 33.5 years compared to 26 in responders (P=0.024). They had higher gamma glutamyl transferase levels (P=0.030) and cirrhosis (P=0.003). Genotype CC was present in 29/40 of response failures compared to 9/17 of the responders (P=0.152). Logistic regression analysis showed that cirrhosis was the independent risk factor for failure to have a response (P=0.001). 4/7 patients with spontaneous clearance had genotype CC. Conclusions: IFNλ3 rs12979860 SNP does not have any significant influence on long-term hepatitis D clearance. Presence of cirrhosis may influence the response.