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Background. Cryptococcosis-associated immune reconstitution inflammatory syndrome (C-IRIS) may be driven by aberrant T-cell responses to cryptococcal antigens. We investigated this in HIV-infected patients with treated cryptococcal meningitis (CM) who commenced combination antiretroviral therapy (cART).Methods. Mitogen- and cryptococcal mannoprotein (CMP)-activated (CD25+CD134+) CD4+ T-cells and induced production of IFN-gamma, IL-10 and CXCL10 were assessed in whole blood cultures, in a prospective study of 106 HIV-CM co-infected patients.Results. Patients with paradoxical C-IRIS (n=27), compared to patients with no neurological deterioration (no-ND; n=63), had lower CMP-induced IFN-gamma production in 24-hour cultures of blood collected pre-cART and 4-weeks post-cART (p=0.0437 and 0.0257, respectively) and lower CMP-activated CD4+ T-cell counts pre-cART (p=0.0178). Patients who survived to 24-weeks had higher proportions of mitogen-activated CD4+ T-cells and higher CMP-induced CXCL10 and IL-10 production in 24-hour cultures pre-cART than patients who did not survive (p=0.0053, 0.0436 and 0.0319, respectively). C-IRIS was not associated with higher CMP-specific T-cell responses before or during cART.Conclusion. Greater preservation of T-cell function and higher CMP-induced IL-10 and CXCL10 production before cART are associated with improved survival on cART. Lower CMP-induced IFN-gamma production pre-cART but not higher CMP-specific T-cell responses after cART were risk factors for C-IRIS.