The lack of early and effective diagnostic procedure, toxicity displayed by the most commonly used fungicidal drugs and emergence of resistant strains responsible for high morbidity and mortality requires an urgent need for vaccination against intracellular pathogens. In the present study, we report the use of γ-irradiated pathogen primed macrophages as an immuneprotective agent against disseminated cryptococcosis. The T-cell proliferation analysis clearly showed that the γ-irradiated pathogen primed macrophages proved to be a better immunestimulatory agent than the cytosolic fraction of C. neoformans. Mice immunized with different vaccine formulations developed CD8+ Tcell mediated Th-1 response as was assessed from the cytokine profiling and IgG isotyping. Protective studies in immunized animals challenged with live C. neoformans showed improved survival rates. However, the protective efficacy was highest in case of animals immunized with xenovaccines as was evaluated with increased survival rate (80%) and decreased fungal burden in the vital organs of the animals compared with control groups and groups of mice immunized with allovaccines or for that matter synvaccines. Together, these suggest that γ-irradiated pathogen harboring xenovaccines could play an active role in imparting protection against experimentally disseminated Cryptococci infection.