Immunosuppression induced by is important in the pathogenesis of active tuberculosis (TB). However, the impact of depressed TB-specific and non-TB-specific gamma interferon (IFN-γ) response on the treatment outcomes of TB patients remains uncertain. In this prospective cohort study, culture- or pathology-proven active TB patients were enrolled and QuantiFERON-TB Gold In-Tube (QFT-GIT) assays were performed before the initiation of anti-TB treatment. TB-specific IFN-γ responses (TB antigen tube subtracted from the nil tube) and non-TB-specific IFN-γ responses (mitogen tube subtracted from the nil tube) were measured and associated with treatment outcomes, including 2-month culture conversion and on-treatment mortality. A total of 212 active TB patients were included in the analysis. We observed a close correlation between decreased lymphocyte count and lower non-TB-specific IFN-γ responses but not TB-specific IFN-γ responses. Patients with lower non-TB-specific IFN-γ responses had lower 2-month culture conversion rate (71.1% versus 84.7%, respectively; = 0.033) and higher on-treatment mortality (22.6% versus 5.7%, respectively; = 0.001) than those with higher non-TB-specific IFN-γ responses. In multivariate analysis, depressed non-TB-specific IFN-γ response was an independent factor associated with 2-month sputum culture nonconversion (odds ratio OR, 2.49; 95% CI 95% confidence interval, 1.05 to 5.90) and on-treatment mortality (hazard ratio HR, 2.76; 95% CI, 1.15 to 6.62). In contrast, depressed TB-specific IFN-γ responses were significantly associated with higher on-treatment mortality in univariate analysis but not in multivariate analysis. Our findings suggest that depressed non-TB-specific responses, but not TB-specific IFN-γ responses, as measured by QFT-GIT before the initiation of anti-TB treatment, were significantly associated with worse treatment outcomes in TB patients.