In the present study, we tried to evaluate the ligands for Toll-like receptor 7 (TLR7) (R-848) and TLR 9 (CpG ODN) as adjuvants to augment the cellular and humoral immune responses as well as the generation of long-lasting immune memories following the vaccination with HBsAg in mice. The immune responses were assessed by enzyme-linked immunosorbent assay (ELISA), enzyme-linked immunospot (ELISPOT), and fluorescence-activated cell sorter (FACS) at the total and at the single-cell levels. Our results showed that CpG ODN or R-848 could enhance HBsAg-specific humoral and cellular immune responses following boosts. When R-848 in combination with CpG was used as adjuvants, the immune responses to HBsAg were further strengthened. Additional analysis demonstrated that the majority of the long-lasting HBsAg-specific T cells displayed effector memory phenotype. Taken together, our results imply that CpG ODN and R-848 may be the candidates as adjuvants for use in prophylactic and therapeutic hepatitis B vaccine.