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. J. Med. Virol. 81:1716–1720, 2009. © 2009 Wiley-Liss, Inc.