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Background: Emerging evidence suggests that shortened, simplified treatment regimens for rifampicin-resistant tuberculosis (RR-TB) can achieve comparable end-of-treatment (EOT) outcomes to longer regimens. We compared a 6-month regimen containing bedaquiline, pretomanid, linezolid, and moxifloxacin (BPaLM) to a standard of care strategy using a 9- or 18-month regimen depending on whether fluoroquinolone resistance (FQ-R) was detected on drug susceptibility testing (DST). Methods and findings: The primary objective was to determine whether 6 months of BPaLM is a cost-effective treatment strategy for RR-TB. We used genomic and demographic data to parameterize a mathematical model estimating long-term health outcomes measured in quality-adjusted life years (QALYs) and lifetime costs in 2022 USD ($) for each treatment strategy for patients 15 years and older diagnosed with pulmonary RR-TB in Moldova, a country with a high burden of TB drug resistance. For each individual, we simulated the natural history of TB and associated treatment outcomes, as well as the process of acquiring resistance to each of 12 anti-TB drugs. Compared to the standard of care, 6 months of BPaLM was cost-effective. This strategy was estimated to reduce lifetime costs by $3,366 (95% UI: [1,465, 5,742] p < 0.001) per individual, with a nonsignificant change in QALYs (−0.06; 95% UI: [−0.49, 0.032] p = 0.790). For those stopping moxifloxacin under the BPaLM regimen, continuing with BPaL plus clofazimine (BPaLC) provided more QALYs at lower cost than continuing with BPaL alone. Strategies based on 6 months of BPaLM had at least a 93% chance of being cost-effective, so long as BPaLC was continued in the event of stopping moxifloxacin. BPaLM for 6 months also reduced the average time spent with TB resistant to amikacin, bedaquiline, clofazimine, cycloserine, moxifloxacin, and pyrazinamide, while it increased the average time spent with TB resistant to delamanid and pretomanid. Sensitivity analyses showed 6 months of BPaLM to be cost-effective across a broad range of values for the relative effectiveness of BPaLM, and the proportion of the cohort with FQ-R. Compared to the standard of care, 6 months of BPaLM would be expected to save Moldova's national TB program budget $7.1 million (95% UI: [1.3 million, 15.4 million] p = 0.002) over the 5-year period from implementation. Our analysis did not account for all possible interactions between specific drugs with regard to treatment outcomes, resistance acquisition, or the consequences of specific types of severe adverse events, nor did we model how the intervention may affect TB transmission dynamics. Conclusions: Compared to standard of care, longer regimens, the implementation of the 6-month BPaLM regimen could improve the cost-effectiveness of care for individuals diagnosed with RR-TB, particularly in settings with a high burden of drug-resistant TB. Further research may be warranted to explore the impact and cost-effectiveness of shorter RR-TB regimens across settings with varied drug-resistant TB burdens and national income levels. Author summary: Why was this study done?: Drug resistance poses a major barrier to the effective treatment of tuberculosis, especially in Moldova and other post-Soviet states which have the highest levels of resistance in the world. Individuals with tuberculosis resistant to the key drug rifampicin face a worse prognosis, a longer and more expensive course of treatment, and more side effects than individuals with rifampicin-susceptible tuberculosis. Until recently, the standard of care for rifampicin-resistant tuberculosis (RR-TB) involved many drugs in combination, often given for 18 months or longer. The newer, 6-month "BPaLM" regimen is comprised of 4 drugs (bedaquiline, pretomanid, linezolid, and moxifloxacin) to which resistance levels are currently low, and while it was shown to be just as effective as the standard of care when health outcomes were measured at 72 weeks from treatment initiation, its effect on lifetime health outcomes, costs, and the acquisition of drug resistance was less clear. What did the researchers do and find?: Using a mathematical model, we projected the lifetime health benefits and costs of the 6-month BPaLM regimen as compared to 9–18 month, standard of care treatments for RR-TB, and found that 6 months of BPaLM would be likely to provide similar health benefits, at lower cost. Compared to the standard of care, we also found that the 6-month BPaLM regimen could shorten the average duration of tuberculosis resistant to the drugs amikacin, bedaquiline, clofazimine, cycloserine, moxifloxacin, and pyrazinamide, while it may increase the average duration of tuberculosis resistant to delamanid and pretomanid. For individuals receiving BPaLM who had to stop taking the drug moxifloxacin, we found that it would likely be beneficial on both health and cost grounds to replace it with clofazimine, thereby topping the regimen back up to 4 drugs. What do these findings mean?: Using conventional benchmarks for value-for-money, we estimated that 6 months of BPaLM would be a cost-effective approach for the treatment of RR-TB in Moldova, and potentially other post-Soviet countries. Though the impact of the 6-month BPaLM regimen on the spread of drug resistance is uncertain and not addressed directly by this study, this combination of newer drugs appears to achieve cure more quickly, thereby reducing the amount of time an individual is potentially infectious. This may be beneficial in fighting resistance to several drugs, even while it may increase the spread of resistance to others. Further studies may be warranted to explore how well these findings would translate to different global regions where health system capabilities, costs, and existing resistance patterns may differ. [ABSTRACT FROM AUTHOR]