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Background Immune defects in chronic pulmonary aspergillosis (CPA) are poorly characterised. We compared peripheral blood cytokine profiles in patients with CPA vs healthy controls and explored the relationship with disease severity. Methods Interferon-gamma (IFNγ), IL-17, TNFα, IL-6, IL-12 and IL-10 were measured after in vitro stimulation of whole blood with lipopolysaccharide (LPS), phytohaemagglutinin (PHA), β-glucan, zymosan (ZYM), IL-12 or IL-18, and combinations. Clinical parameters and mortality were correlated with cytokine production. Results Cytokine profiles were evaluated in 133 patients (57.1% male, mean age 61 years). In comparison to controls, patients with CPA had significantly reduced production of IFNγ in response to stimulation with β-glucan+IL-12 (312 vs 988 pg/ml), LPS+IL-12 (252 vs 1033 pg/ml), ZYM+IL-12 (996 vs 2347 pg/ml), and IL-18+IL-12 (7193 vs 12330 pg/ml). Age >60 (p=0.05, HR 1.71, 95%CI 1.00-2.91) and COPD (p=0.039, HR 1.69, 95%CI 1.03-2.78) were associated with worse survival, whereas high IFNγ production in response to beta-glucan+IL-12 stimulation (p=0.026, HR 0.48, 95%CI 0.25-0.92) was associated with reduced mortality. Conclusion Patients with CPA show impaired IFNγ production in peripheral blood in response to stimuli. Defective IFNγ production ability correlates with worse outcomes. Immunotherapy with IFNγ could be beneficial for patients showing impaired IFNγ production in CPA.