BACKGROUND: Systemic levels of interleukin (IL)-7 at antiretroviral therapy (ART) initiation have previously been shown to be predictive of HIV-linked paradoxical cryptococcosis-associated immune reconstitution inflammatory syndrome (C-IRIS). We therefore explored IL-7/IL-7 receptor (IL-7/IL-7R) signaling pathway dysfunction, with related alterations in immune function, as a mechanism underlying C-IRIS. METHOD: HIV-infected patients with cryptococcal meningitis who experienced C-IRIS (n = 27) were compared with CD4 T-cell count-matched counterparts without C-IRIS (n = 27), after antifungal therapy and pre-ART initiation. Flow cytometry was used to assess T-cell and monocyte phenotypes and functions. RESULTS: Proportions of IL-7R+ CD4 or CD8 T cells correlated positively with CD4 T-cell counts and proportions of central memory and naive CD4 and CD8 T-cell pre-ART (all r > 0.50 and P < 0.05); however, the former negatively correlated with CD4 T-cell counts fold-increase on ART in non-C-IRIS but not C-IRIS patients. Higher frequencies of activated monocytes (CD14CD86 or CD14+HLA-DR+; P ≤ 0.038) were also observed in C-IRIS compared with non-C-IRIS patients, and those who failed to clear cryptococci from cerebrospinal fluid before ART had higher levels of activated monocytes (CD14+HLA-DR+, P = 0.017) compared with those who cleared. In multivariate regression, CD14+HLA-DR+ monocytes were independently associated with C-IRIS [hazard ratio = 1.055 (1.013-1.098); P = 0.009]. CONCLUSION: In contrast to non-C-IRIS patients, C-IRIS patients displayed a lack of association between proportions of IL-7R+ T cells and several markers of T-cell homeostasis. They also exhibited higher monocyte activation linked to cerebrospinal fluid cryptococcal culture positivity before ART. These data suggest a role for IL-7/IL-7R signaling pathway dysregulation in the pathogenesis of C-IRIS, possibly linked to monocyte activation and residual pathogen burden before ART.