Immunization with plasma membrane vesicles (PMVs) engrafted into liposomes (PMV+Lip) can potentiate the protective immune responses against a wide range of antigens present within the PMVs. In the present study Leishmania -derived PMVs were engrafted into liposomes using freeze-drying method and the immunogenicity and protective efficacy of engrafted particles in BALB/c mice were evaluated by determining serum levels of anti-parasite IgG isotypes, cytokine profiles, footpad thickness and parasite burden. The results showed that ten weeks after challenge with parasites, the IgG2a/IgG1 ratio as well as the levels of IFN-γ production, reflecting a Th1 response, were significantly higher in mice vaccinated with PMV+Lip compared to PMVs-immunized control group (for IFN-γ: 15312±2429 pg/ml and 12181±1240 pg/ml, respectively; p= 0.035). By contrast, the levels of Th2-dependent cytokines (IL-5 and IL-10) in mice vaccinated with PMV+Lip were significantly lower compared to those that received PMV alone (IL-5: 113±24 pg/ml and 245±94 pg/ml, respectively, p<0.01; IL-10: 2145±311 pg/ml and 3290±533 pg/ml, respectively, p<0.001). In vivo results also showed a significant reduction in the number of parasites in the spleen, as well as decreased footpad swelling in PMV+Lip immunized mice compared to the PMV group (for parasite burden: (1.9×105±2.4×105 and 1.84×106±8×105, respectively; p=0.01). In conclusion, engraftment of Leishmania-derived PMVs into liposomes can be considered as an effective and promising method for vaccine development against Leishmaniasis.