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: Introduction: In 2017, the Aurum Institute, with support from Unitaid, launched an initiative to expand short‐course therapy for the prevention of tuberculosis (TB) in 12 high‐burden countries. This study aimed to investigate the importance of “catalytic” effects beyond the original project timeframe when estimating cost‐effectiveness of such large investments. Methods: We estimated the cost‐effectiveness of the IMPAACT4TB (I4TB) initiative from a health system perspective, using a 10‐year time horizon. We first conservatively estimated costs using a “top‐down” approach considering only the direct health benefits of providing TB preventive therapy to people initiating antiretroviral therapy (ART) through I4TB activities. We then re‐estimated the incremental cost‐effectiveness of I4TB incorporating the costs and health benefits of potential catalytic effects beyond the program itself. Results: We estimated that TB preventive therapy through the I4TB initiative alone would prevent 14 201 cases of active TB and 1562 TB deaths over 10 years with an up‐front investment of $52.5 million; the estimated incremental cost‐effectiveness was $1580 per disability‐adjusted life year (DALY) averted. If this initiative could achieve its desired catalytic effects, an additional 375 648 cases and 41 321 deaths could be averted, at an incremental cost of $546 million and cost‐effectiveness of $713 per DALY averted. Conclusions: Our findings provide donors with reasonable evidence of value for money to support investment in short‐course TB preventive therapy for people initiating ART in high‐burden settings. Our study also illustrates the importance of considering long‐term secondary (“catalytic”) effects when evaluating the cost‐effectiveness of large‐scale initiatives designed to change a global policy landscape., INTRODUCTION Since 1993, the World Health Organization (WHO) has recommended preventive therapy for tuberculosis (TB) for people living with HIV (PLHIV) in whom active TB has been excluded (without testing [...]