BACKGROUND: Initiation of antiretroviral therapy (ART) in human immunodeficiency virus patients with treated or unrecognized Mycobacterium tuberculosis infection may result in tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) or ART-associated tuberculosis (ART-TB), respectively. Both conditions appear to be immune restoration disease but their immunopathogenesis is not completely understood. METHODS: Chemokines and cytokines produced by the innate immune system (CCL2, CXCL8, CXCL9, CXCL10, and interleukin 18 [IL-18]) were assayed in plasma from unstimulated whole blood cultures obtained from 15 TB-IRIS case patients, 11 ART-TB case patients, and matched control participants over 24 weeks of ART. RESULTS: When compared with control participants, levels of IL-18 and CXCL10 were higher in TB-IRIS case patients (P = .002 and .006, respectively), whereas CCL2 was lower (P = .006). IL-18 level was higher in ART-TB case patients (P = .002), but CXCL10 was only marginally higher (P = .06). When TB-IRIS case patients were compared with ART-TB case patients, IL-18 was higher in ART-TB (P = .03), whereas CXCL10 was higher in TB-IRIS (P = .001). Using receiver operating characteristic curves, pre-ART levels of CCL2, CXCL10, and IL-18 were predictive of TB-IRIS and additive to IFN-gamma responses. CONCLUSIONS: Perturbations of the innate immune response to M. tuberculosis before and during ART may contribute to the immunopathology of TB-IRIS, whereas elevated IL-18 alone suggests adaptive immune responses predominate in ART-TB. These findings may have implications for therapy in TB-IRIS.