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Background: Multiple host blood transcriptional signatures have been developed as non-sputum triage tests for tuberculosis (TB). We aimed to compare the diagnostic performance of 20 blood transcriptomic TB signatures for differentiating between symptomatic patients who have TB versus other respiratory diseases (ORD)., Methods: As part of a nested case-control study, individuals presenting with respiratory symptoms at primary healthcare clinics in Ethiopia, Malawi, Namibia, Uganda, South Africa and The Gambia were enrolled. TB was diagnosed based on clinical, microbiological and radiological findings. Transcriptomic signatures were measured in whole blood using microfluidic real-time quantitative PCR. Diagnostic performance was benchmarked against the World Health Organization Target Product Profile (TPP) for a non-sputum TB triage test., Results: Among 579 participants, 158 had definite, microbiologically confirmed TB, 32 had probable TB, while 389 participants had ORD. Nine signatures differentiated between ORD and TB with equivalent performance (Satproedprai7: area under the curve 0.83 (95% CI 0.79-0.87); Jacobsen3: 0.83 (95% CI 0.79-0.86); Suliman2: 0.82 (95% CI 0.78-0.86); Roe1: 0.82 (95% CI 0.78-0.86); Kaforou22: 0.82 (95% CI 0.78-0.86); Sambarey10: 0.81 (95% CI 0.77-0.85); Duffy9: 0.81 (95% CI 0.76-0.86); Gliddon3: 0.8 (95% CI 0.75-0.85); Suliman4 0.79 (95% CI 0.75-0.84)). Benchmarked against a 90% sensitivity, these signatures achieved specificities between 44% (95% CI 38-49%) and 54% (95% CI 49-59%), not meeting the TPP criteria. Signature scores significantly varied by HIV status and country. In country-specific analyses, several signatures, such as Satproedprai7 and Penn-Nicholson6, met the minimal TPP criteria for a triage test in Ethiopia, Malawi and South Africa., Conclusion: No signatures met the TPP criteria in a pooled analysis of all countries, but several signatures met the minimum criteria for a non-sputum TB triage test in some countries., Competing Interests: Conflict of interest: G. Walzl and T.J. Scriba report grants from the Bill & Melinda Gates Foundation during the conduct of the study. T.J. Scriba and N.N. Chegou report grants from the South African Medical Research Council during the conduct of the study. G. Walzl reports grants from the South African National Research Foundation and EDCTP. T.J. Scriba has patents of the RISK11 (Darboe11), RISK6 (Penn-Nicholson6) and RISK4 (Suliman4) signatures issued. G. Walzl and N.N. Chegou have patents “TB diagnostic markers” (PCT/IB2013/054377), “Serum host biomarkers for tuberculosis disease” (PCT/IB2017/052142) and “Method for diagnosing TB” (PCT/IB2017/052142) granted but receive no royalties on these patents. The remaining authors have no potential conflicts of interest to disclose., (Copyright ©The authors 2024.)