Context: Upper airway suctioning at birth was considered standard procedure and is still commonly practiced. Negative effects could exceed benefits of suction. Question: In infants born through clear amniotic fluid (P) does suctioning of the mouth and nose (I) vs no suctioning (C) improve outcomes (O). Data sources: Information specialist conducted literature search (12th September 2021, re-run 17th June 2022) using Medline, Embase, Cochrane Databases, Database of Abstracts of Reviews of Effects, and CINAHL. RCTs, non-RCTs and observational studies with a defined selection strategy were included. Unpublished studies, reviews, editorials, animal and manikin studies were excluded. Data extraction: Two authors independently extracted data, risk of bias was assessed using the Cochrane ROB2 and ROBINS-I tools. Certainty of evidence was assed using the GRADE framework. Review Manager was used to analyse data and GRADEPro to develop summary of evidence tables. Meta-analyses were performed if ≥2 RCTs were available. Outcomes: Primary: assisted ventilation. Secondary: advanced resuscitation, oxygen supplementation, adverse effects of suctioning, unanticipated NICU admission. Results: Nine RCTs (n = 1096) and 2 observational studies (n = 418) were identified. Two RCTs (n = 280) with data concerns were excluded post-hoc. Meta-analysis of 3 RCTs, (n = 702) showed no difference in primary outcome. Two RCTs (n = 200) and 2 prospective observational studies (n = 418) found lower oxygen saturations in first 10 minutes of life with suctioning. Two RCTs (n = 200) showed suctioned newborns took longer to achieve target saturations. Limitations: Certainty of evidence was low or very low for all outcomes. Most studies selected healthy newborns limiting generalisability and insufficient data was available for planned subgroup analyses. Conclusions: Despite low certainty evidence, this review suggests no clinical benefit from suctioning clear amniotic fluid from infants following birth, with some evidence suggesting a resulting desaturation. These finding support current guideline recommendations that this practice is not used as a routine step in birth. Funding: The International Liaison Committee on Resuscitation provided access to software platforms, an information specialist and teleconferencing. Clinical Trial Registration: This systematic review was registered with the Prospective Register of Systematic Reviews (https://www.crd.york.ac.uk/prospero/) (identifier: CRD42021286258).