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13 Pages, 1 Figure, 4 tables. The authors' affiliations are listed in the Supplementary Appendix, available at NEJM.org. Supplementary Material, available at http://dx.doi.org/10.1056/NEJMoa1800474 ; BACKGROUND: The World Health Organization recommends drug-susceptibility testing of Mycobacterium tuberculosis complex for all patients with tuberculosis to guide treatment decisions and improve outcomes. Whether DNA sequencing can be used to accurately predict profiles of susceptibility to first-line antituberculosis drugs has not been clear. METHODS: We obtained whole-genome sequences and associated phenotypes of resistance or susceptibility to the first-line antituberculosis drugs isoniazid, rifampin, ethambutol, and pyrazinamide for isolates from 16 countries across six continents. For each isolate, mutations associated with drug resistance and drug susceptibility were identified across nine genes, and individual phenotypes were predicted unless mutations of unknown association were also present. To identify how whole-genome sequencing might direct first-line drug therapy, complete susceptibility profiles were predicted. These profiles were predicted to be susceptible to all four drugs (i.e., pansusceptible) if they were predicted to be susceptible to isoniazid and to the other drugs or if they contained mutations of unknown association in genes that affect susceptibility to the other drugs. We simulated the way in which the negative predictive value changed with the prevalence of drug resistance. RESULTS: A total of 10,209 isolates were analyzed. The largest proportion of phenotypes was predicted for rifampin (9660 [95.4%] of 10,130) and the smallest was predicted for ethambutol (8794 [89.8%] of 9794). Resistance to isoniazid, rifampin, ethambutol, and pyrazinamide was correctly predicted with 97.1%, 97.5%, 94.6%, and 91.3% sensitivity, respectively, and susceptibility to these drugs was correctly predicted with 99.0%, 98.8%, 93.6%, and 96.8% specificity. Of the 7516 isolates with complete phenotypic drug-susceptibility profiles, 5865 (78.0%) had complete genotypic predictions, among which 5250 profiles (89.5%) were correctly predicted. Among the 4037 phenotypic profiles that were predicted to be pansusceptible, 3952 (97.9%) were correctly predicted. CONCLUSIONS: Genotypic predictions of the susceptibility of M. tuberculosis to first-line drugs were found to be correlated with phenotypic susceptibility to these drugs. (Funded by the Bill and Melinda Gates Foundation and others.). ; Supported by grants from the Bill and Melinda Gates Foundation (OPP1133541, to CRyPTIC, plus separate support to Dr. Rodwell), a Wellcome Trust/Newton Fund–MRC Collaborative Award (200205/Z/15/Z, to CRyPTIC), the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre (BRC) and NIHR Health Protection Research Unit in Healthcare Associated Infections and Antimicrobial Resistance at University of Oxford in partnership with Public Health England, the NIHR Biomedical Research Centre at Barts, the NIHR Biomedical Research Centre at Imperial, the NIHR and NHS England (to the 100,000 Genomes Project, which is managed by Genomics England, a wholly owned company of the U.K. Department of Health), the Wellcome Trust, the Medical Research Council, Public Health England, a grant from the National Science and Technology Key Program of China (2014ZX10003002), a grant from the National Basic Research program of China (2014CB744403), a grant from the Strategic Priority Research Program of the Chinese Academy of Sciences (XDB29020000), a grant from the European Commission Seventh Framework Program (FP7/2007-2013, to Borstel under grant agreement 278864 in the framework of the Patho-NGen-Trace project), the German Center for Infection Research (to Borstel), Leibniz Science Campus Evolutionary Medicine of the Lung (EvoLUNG), the Belgian Ministry of Social Affairs (to the Belgian Reference Center for Tuberculosis and Mycobacteria from Bacterial Diseases Service through a fund within the Health Insurance System), the French governmental program "Investing for the Future" (to Genoscreen), a grant from the European Commission Seventh Framework Program (FP7/2007-2013, to Genoscreen under grant agreement 278864 in the framework of the Patho-NGen-Trace project), grants from the Drug Resistant Tuberculosis Fund (R015833003, to Dr. Chaiprasert), the Faculty of Medicine, Siriraj Hospital, Mahidol University (to Dr. Chaiprasert), a grant from the Ministry of Economy and Competitiveness (MINECO), Spain (SAF2016-77346-R, to Dr. Comas), a grant from the European Research Council (638553-TB-ACCELERATE, to Dr. Comas), a grant from the BC Centre for Disease Control Foundation for Population and Public Health (to Dr. Gardy), a grant from the British Colombia Lung Association (to Dr. Gardy), grants from the Wellcome Trust and the Royal Society (101237/Z/13/Z and 102541/A/13/Z, to Drs. Wilson and Iqbal [Sir Henry Dale Fellows]), a grant from the National University of Singapore Yong Loo Lin School of Medicine Aspiration Fund (NUHSRO/2014/069/AF-New Idea/04, to Drs. Ong and Teo), a European Commission Seventh Framework Program European Genetic Network (EUROGEN) grant (201483, to Dr. Drobniewski), and the National Institute of Allergy and Infectious Diseases, National Institutes of Health (to Dr. Rodwell). Dr. T. Walker is an NIHR Academic Clinical Lecturer, and Drs. Crook, Peto, and Caulfield are NIHR Senior Investigators. No potential conflict of interest relevant to this article was reported. Disclosure forms provided by the authors are available with the full text of this article at NEJM.org. We thank Stéphanie Duthoy, Carina Hahn, Alamdar Hussain, Yannick Laurent, Mathilde Mairey, Vanessa Mohr, and Mahmood Qadir for technical assistance and George F. Gao, Director of the Chinese Center for Disease Control and Prevention, for directing the Chinese grant and sequencing program ; Peer reviewed