Hepatitis B virus (HBV) genotype D and hepatitis B e antigen (HBeAg) negative chronic hepatitis are the most prevalent in Mediterranean countries. No data have ever been published on their prevalence in Syria, a country of intermediate endemicity for HBV. The aims of the current study were to determine the HBV genotype distribution in Syria, the prevalence of HBeAg-positive and HBeAg-negative chronic hepatitis and to analyse the clinical characteristics of each group. A total of 220 patients were included. Ninety-seven percent of the patients were of genotype D, and 72% were HBeAg negative. The HBeAg-negative patients were older, had a lower viral load, had more cirrhosis and the mode of contamination was known less than for HBeAg-positive patients. These findings have major implications in understanding the natural history of the infection and are of great relevance in the choice of therapy.