BACKGROUND Invasive fungal infections (IFI) in immunocompromised patients are associated with significant morbidity and mortality, despite appropriate antifungal treatment and recovery from neutropenia. The outcome of these infections depends significantly on the overall state of immunosuppression, including mainly the phagocytic system (neutrophils and macrophages). Interferon-gamma (IFN-gamma), granulocyte-colony--stimulating factor (G-CSF) and granulocyte-macrophage-colony--stimulating factor (GM-CSF) are cytokines that enhance the activity of neutrophils and macrophages. METHODS The authors reported 4 patients with leukemia and refractory invasive candidiasis or trichosporonosis despite 1-13 months of appropriate antifungal treatment. RESULTS Cytokines were administered for 1.5-5 months without significant toxicity. For each patient, initiation of interferon-gamma plus a colony-stimulating factor resulted in a clinical response. The contribution of cytokines to control the fungal infection in these 4 patients was suggested by the strong inflammatory reaction observed in the 2 patients who had an immediate response (within 7 days of initiation of cytokine therapy) and by the good outcome in the 2 other patients in whom antifungal agents were discontinued at the start of cytokine therapy. CONCLUSIONS These data suggested a potential role for immunomodulation in patients with leukemia with refractory invasive fungal infections.