Background: In many settings, the benefits of antiretroviral therapy (ART) are reduced by the high early incidence of tuberculosis and tuberculosis- associated immune reconstitution inflammatory syndrome (TB-IRIS). Methods: We used tuberculin skin testing and the QuantiFERON-TB Gold In-Tube assay to investigate cellular immune responses to purified protein derivative (PPD) and region of difference 1 (RD1) antigens during the first 24 weeks of ART. Results: TB-IRIS and ART-associated tuberculosis occurred in 15 of 75 (20%) and 11 of 231 (4.8%) participants at risk, respectively. Greater increases in interferon γ (IFN-γ) and skin test responses to PPD were seen at week 24 and 12 in participants with TB-IRIS (P ≤ .04), respectively. Raw IFN-γ responses to RD1 antigens and PPD corrected for pre-ART CD4+ T cell counts were higher at all time points in individuals with ART-associated tuberculosis (P ≤ .001) and were associated with areas under receiver operator characteristic curves of 0.90 for RD1 (95% confidence interval [CI], 0.78-1.00) and 0.92 for PPD (95% CI, 0.83-1.00) for the diagnosis of ARTassociated tuberculosis. Pre-ART IFN-γ responses enabled stratification of participants into groups with risks of subsequent tuberculosis of 0.7%, 9.3%, and 30.0%. Conclusions: Type 1 effector T cell responses are prominent in ART-associated tuberculosis, but additional immune defects may be more important in paradoxical TB-IRIS. IFN-γ release assays may contribute to the prediction and diagnosis of tuberculosis during early ART.