OBJECTIVES: The prevalence of tuberculosis (TB) and latent tuberculosis infection (LTBI) among mental patients is higher than that of the general　population. Smokers have an increased risk of reactivating LTBI, TB recurrence and death. Interferon-gamma release assays (IGRAs); QuantiFERON-TB® Gold In-Tube (QFT) and T-SPOT®.TB (T-SPOT), are new alternatives to the tuberculin skin test (TST) to detect LTBI with higher sensitivities and specificities. This study aimed to assess the cost effectiveness for TB screening of mental patients with tobacco smoking using IGRAs compared to TST and chest X-ray (CXR).  METHODS: Decision trees and Markov models were constructed with seven strategies; QFT, T-SPOT, TST, TST followed by QFT, TST followed by T-SPOT, CXR and no screening. 30-years-old mental patients with and without tobacco smoking were chosen as a hypothetical cohort using a societal perspective on a lifetime horizon. Incremental cost per quality adjusted life year (QALY) gained ratios were compared. All costs and clinical benefits were discounted at a fixed annual rate of 3%. RESULTS: In base-case analysis, TST followed by QFT strategy was the most cost-effective among mental patients. No screening and CXR strategies were less cost-effective. Cost-effectiveness was sensitive to LTBI rate and BCG vaccination rate among non-smokers. No screening strategy was more cost-effective than TST followed by QFT strategy at the willingness to pay level of $US 100,000/QALY gained when LTBI rate among non-smokers was less than 0.10. The QFT strategy was more cost-effective than TST followed by QFT strategy at the willingness to pay level of $US 100,000/QALY gained when BCG vaccination rate among non-smokers was less than 0.18. CONCLUSIONS: TB screening using an IGRA for mental patients is recommended on the basis of the cost-effectiveness, especially with tobacco smoking. This suggests that further supporting tobacco cessation intervention for smoking mental patients is beneficial to control TB.