Background: Most studies evaluating the effect of Xpert MTB/RIF testing for tuberculosis (TB) concluded that it did not reduce overall mortality compared to usual care. We conducted a systematic review to assess whether key study design and execution features contributed to earlier identification of patients with TB and decreased pre-treatment loss to follow-up, thereby reducing the potential impact of Xpert MTB/RIF testing. Methods: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, and Scopus for literature published from 1 st January 2009 to February 2019. We included all primary intervention studies that had evaluated the effect of Xpert MTB/RIF on mortality compared to usual care in participants with presumptive pulmonary TB. We critically reviewed features of included studies across: Study setting and context, Study population, Participant recruitment and enrolment, Study procedures, and Study follow-up. Results: We included seven randomised and one non-randomised study. All included studies demonstrated relative reductions in overall mortality in the Xpert MTB/RIF arm ranging from 6% to 40%. However, mortality reduction was reported to be statistically significant in two studies. Study features that could explain the lack of observed effect on mortality included: the higher quality of care at study sites; inclusion of patients with a higher pre-test probability of TB leading to higher than expected empirical rates; performance of additional diagnostic testing not done in usual care leading to increased TB diagnosis or empiric treatment initiation; the recruitment of participants likely to return for follow-up; and involvement of study staff in ensuring adherence with care and follow-up. Conclusion: Most studies of Xpert MTB/RIF were designed and conducted in a manner that resulted in more patients being diagnosed and treated for TB, minimising the potential difference in mortality Xpert MTB/RIF testing could have achieved compared to usual care.