Background. Improving immune responses to vaccination in immunosuppressed patients is extremely important. Previously, we observed that cyclosporine (CsA) combined with a nonlytic interleukin (IL)-2/fragment crystallizable (Fc) fusion protein induces immune tolerance to mouse skin transplantations. In the present study, we asked whether this combination improved hepatitis B (HBV) vaccine efficacy in immunosuppressed mice while also prolonging skin graft survival. Methods. After C57BL/6 mice received DBA/2 skin grafts, they were administered a 14-day course of CsA (30 mg/kg intraperitoneal) combined with IL-2/Fc (1 mu g, intraperitoneal). HBV vaccine (2 mu g) was injected intramuscularly on the day of skin transplantation. On day 14, the serum levels of hepatitis B surface antibody (HBsAb), IL-4, IL-10, interferon (IFN-gamma), and IL-2 were measured by enzyme-linked immunosorbent assay. We assessed the percentages of CD4(+)CXCR5(+) follicular T helper cells, CD4(+)FoxP3(+) regulatory T cells (Treg) and expressions of IL-17, IL-21, FoxP3, Bcl-6 in the spleen. Animals were divided into four groups: control, vaccine-treated, CsA vaccine-treated, CsA + IL-2/Fc + vaccine-treated hosts. Results. Combination therapy significantly increased HBsAb levels and also prolonged skin graft survival. Serum levels of Th1 cytokines IL-2 and IFN-gamma were significantly higher in the combination group, while Th2 cytokines, IL-4 and IL-10 were lower. Combined treatment increased the percentage of Treg and the expression of Foxp3 and IL-21, meanwhile inhibiting the expression of Bcl-6. But the percentage of Tfh did not significantly change among the groups. Conclusions. These observations suggested that a combination of CsA and IL-2/Fc fusion protein enhanced immune responses after HBV vaccination and prolonged skin graft survival.