Aim of the study: Evaluation of possible associations of single nucleotide polymorphisms upstream the interferon-lambda 3 (IL28B) gene with the phases of HBeAg-negative chronic hepatitis B virus (HBV) genotype D infection and with patient outcomes in a Caucasian population. Materials and methodology: The IL-28B rs12979860 polymorphisms were evaluated in 400 Greek patients with HBeAg-negative chronic HBV infection genotype D (n=311 with chronic hepatitis B, n=89 inactive HBsAg carriers) and a control group of 222 healthy adults of the same race and ethnicity. Associations with the phase of the infection, response to interferon and/or nucleos(t)ide analogue (NA) therapy, development of hepatocellular carcinoma (HCC) and spontaneous HBsAg clearance were investigated. Results: The distribution of IL28B genotypes and C and T allele frequency among the overall cohort of patients with chronic HBV infection was not statistically different from the general population. In males inactive HBsAg carriers the CC genotype (59%) and C allele (74.5%) were statistically significantly more prevalent compared to chronic hepatitis B patients (37.7%, p= 0.028 and 59.5%, p=0.005, respectively) and the general population (31.4 %, p=0.018 and 58%, p=0.005, respectively). There was no association between IL28B polymorphisms and allele frequencies with spontaneous HBsAg clearance, response to treatment or development of HCC. Conclusions: IL28B polymorphisms at rs12979860 alone do not appear to play any role in the spontaneous or treatment related outcomes of HBeAg-negative genotype D infection in Caucasians, but the possibility that CC genotype and C allele favor the development of the inactive HBsAg carrier state in males should be further investigated.