Individual susceptibility differences to fungal infection following invasive and/or immunosuppressive medical interventions are an important clinical issue. In order to explore immune response-related factors that may be linked to fungal infection susceptibility， we have compared the response of inbred C57BL/6J and outbred CD1 mouse strains to different experimental models of fungal sepsis. The challenge of animals with the zymosan-induced generalised inflammation model revealed poorer survival rates in C57BL/6J， consistent with lower Th1 cytokine interferon (IFN)-γ serum levels， compared with CD1 mice. Likewise， ex vivo exposure of C57BL/6J splenocytes to zymosan but also bacterial lipopolisaccharide or lipoteichoic acid， resulted in lower IFN-γ secretion compared with CD1 mice. C57BL/6J susceptibility could be reverted by rescue infusion of relative low IFN-γ doses (0.2 μg/kg) either alone or in combination with the ß-glucan-binding CD5 protein (0.7 mg/kg) leading to improved post zymosan-induced generalised inflammation survival. Similarly， low survival rates to systemic Candida albicans infection (2.86 × 10  CFU/gr) were ameliorated by low-dose IFN-γ infusion in C57BL/6J but not CD1 mice. Our results highlight the importance of strain choice in experimental fungal infection models and provide a susceptibility rationale for more specific antifungal immunotherapy designs.