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Vaccination with Hepatitis B surface antigen (HBsAg) is being used to prevent HBV infection. The fact that 10% of vaccinees fail to develop protective antibodies has fostered a large body of research for more effective vaccination strategies. Search for new adjuvant, able to selectively trigger protective antibody production, is one of the most promising approaches. The oligosaccharide beta-(1-->6)-branched beta-(1-->3) glucohexaose is the basic unit of lentinan and several other fungal beta-glucans with immunostimulatory activity. beta-glucans stimulate innate immune response mainly through interaction with myeloid cells (macrophages) and dendritic cells. In this study, the ability of synthetic beta-(1-->6)-branched beta-(1-->3) glucohexaose analogue (beta-glu6) to enhance the immune response to HBsAg has been evaluated. Administration of synthetic beta-glu6 i.p. in BALB/c mice greatly enhanced the mobilisation and maturation of macrophages and dendritic cells to co-administered HBsAg, as compared to the antigen alone. The adjuvant effect of beta-glu6 was evident in the increase of T and B cell activation in response to HBsAg, as judged by the percentage of CD69-positive CD4(+) and CD19(+) lymphocytes in the spleen. beta-glu6 could significantly enhance the number of IL-4-producing cells in response to HBsAg, while it had no effect on the number of IFN-gamma-producing lymphocytes, suggesting a Th2 bias of the immune response. The correlate of protection for HBV vaccination, i.e. the titer of HBsAg-specific antibodies, was greatly enhanced by the use of beta-glu6 as a vaccine adjuvant. The IgG1/IgG2a ratio within the anti-HBsAg antibodies was higher in the mice immunised with HBsAg plus beta-glu6 than receiving HBsAg alone or mice administered HBsAg with Freund's adjuvant, indicating a shift towards a Th2-biased anti-inflammatory protective antibody response.