We reported previously that yeast-derived whole glucan particles (WGPs), with or without conjugation to BSA, used as a vaccine protected against systemic aspergillosis in mice. Here, we examined their utility as a potential vaccine against coccidioidomycosis. WGPs were prepared from Saccharomyces cerevisiae; conjugation with BSA (WGP-BSA) was done using 1-cyano-4-dimethylaminopyridinium tetrafluoroborate-mediated conjugation. Heat-killed S. cerevisiae (HKY) was used as a positive-control vaccine. CD-1 mice were vaccinated with WGPs or WGP-BSA, HKY or PBS once weekly, beginning 21 days prior to infection. Mice were infected intravenously with arthroconidia of Coccidioides posadasii. In the low-mortality study, 50 % of PBS-treated controls died. Only WGP-BSA at 0.6 mg per dose induced significant protection compared with PBS treatment. All surviving mice were infected in all three organs examined. Those given WGP-BSA at 0.6 mg per dose had fewer c.f.u. in liver and lungs (P = 0.04), and those given WGPs at 6 mg per dose had fewer in lungs (P < 0.02), compared with PBS. In the high-mortality study, 90 % of PBS mice died. Vaccination with HKY, and WGPs or WGP-BSA at 6 or 12 mg per dose significantly prolonged survival (P ≤ 0.05). No surviving mice were free of infection. HKY and WGP-BSA at 12 mg per dose reduced c.f.u. in the liver and lungs (P < 0.05) and WGP-BSA at 6 mg per dose reduced c.f.u. in the lungs (P < 0.05); unconjugated WGPs did not reduce infection. WGPs or WGP-BSA acted as a vaccine that protected against mortality caused by coccidioidomycosis. Thus, WGP protection against coccidioidomycosis and aspergillosis provides the basis for development of a pan-fungal vaccine.