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Highlights • Potential detrimental non-specific effects of DTwP are controversial. • Diverse relative risks (RRs) of mortality after DTwP in low-income settings. • Meta-regression to explore impact of risk of bias and confounding on RRs. • Increased RR might be confined to West-African countries. • Bias and confounding cannot be ruled out as explanation of the increased RRs. Abstract Introduction It has been suggested that some vaccines have effects beyond protection against the diseases they target, called non-specific effects (NSEs). In 2016, a systematic review by Higgins et al., commissioned by the WHO Strategic Advisory Group of Experts (SAGE) on immunization, estimated the relative risk (RR) of all-cause mortality after whole-cell Diphtheria-Tetanus-Pertussis (DTwP) vaccination to be 1.38 (95% CI: 0.92–2.08), and described these potential NSEs as inconsistent. However, the selection of studies for meta-analysis, based on their proneness to bias and confounding, was debated. Objective To identify study characteristics and postulated risks of bias and confounding that might have impacted the RR of all-cause mortality after DTwP vaccination in observational studies conducted in low-income countries. Methods Based on methodological considerations on study design and analysis, we systematically assessed all 17 DTwP studies from the Higgins et al. review for risk of selection bias, exposure and outcome misclassification, confounding and differential co-interventions. We used meta-regression to assess the impact of study characteristics and the postulated risks of bias and confounding on the RR estimates, and looked for outlying and influential risk estimates. Permutation tests were performed to control for false-positive findings. Results The overall RR of all-cause mortality after DTwP vaccination including all but one outlying and influential study was 1.32 (95% CI: 0.83–2.08). Based on uni-variable meta-regression, we found that study location (p = 0.01), studies using the landmark approach (p = 0.015) and studies at high risk of exposure misclassification (p = 0.036) were significantly associated with increased RR estimates whereas studies at high risk of selection bias (p = 0.059) showed borderline significance. The results further suggest these effect modifiers are clustered in studies conducted in West-Africa. Conclusion The increased RR of all-cause mortality after DTwP might be confined to West-African countries and/or certain postulated risks of bias might have inflated these RRs. [ABSTRACT FROM AUTHOR]