No data on antiviral response of HBV genotypes E-H are available so far although these HBV genotypes contribute significantly to the global HBV burden. Of 49 patients with HBV genotypes E-H, 23 received interferon (IFN)-alpha, 12 nucleos(t)ide analogues and 14 patients were untreated. HBV genotype was determined by direct sequencing of the HBV S gene. Sustained virological response in IFN-treated patients was defined as normalization of ALT and decrease of HBV-DNA <4,000 IU/ml 6 months after treatment. Virological response with nucleos(t)ide analogues was assumed in patients with a HBV-DNA <200 IU/ml after 48 weeks of treatment. HBV genotype E was found in 61.2% (n = 30), HBV genotype F in 8.2% (n = 4), HBV genotype H in 10.2% (n = 5) of patients. Among patients with HBV genotype G (20.4%; n = 10) there were four HBV genotype G/A and three HBV genotype G/C co-infections. Patients had Caucasian (43%), African (55%), or Asian (2%) background. End of treatment response was 70% (16/23) and sustained virological response was 35% (8/23) for patients treated with IFN-alpha. Sustained virological response was 36% for HBV genotype E (n = 5/14), 50% for HBV genotype F or H (n = 2/4), and 20% for HBV genotype G (n = 1/5). Virus suppression at week 48 was achieved in 67% of patients treated with nucleos(t)ide analogues. According to the present preliminary data HBV genotypes E, F, and H appear to be sensitive to IFN-alpha. Lower rates of response to IFN-alpha in patients with HBV genotype G might be related to the frequent occurrence of double infection.