Systematic reviews are commonly used in human health research to provide overviews of existing evidence pertinent to clearly formulated specific questions, using pre-specified and standardised methods to identify and critically appraise relevant research, and to collect, report and analyse data from the studies that are included in the reviews. Formal systematic reviews have rarely been used in food and feed safety risk assessments and the existing systematic review methods in other disciplines may not be directly applicable in this field. This Guidance aims to assist the application of systematic reviews to food and feed safety risk assessments in support of decision making, by describing a framework for identifying the different types of question suitable for systematic review generated by the risk assessment process and for determining the need for systematic reviews when dealing with broad food and feed safety policy problems. The Guidance provides suggestions and examples for the conduct of eight key steps in the systematic review process (preparing a review, searching for studies, selecting studies for inclusion, collecting data from included studies, assessing the methodological quality of included studies, synthesising data from the studies, presenting data and results, and interpreting the results and drawing conclusions) for questions suitable for systematic reviews, taking into account issues that may be unique to food and feed safety. Due to its methodological rigor and its objective and transparent nature, systematic review methodology and its principles could provide additional value for answering well-formulated specific questions generated by the risk assessment process or other analytical frameworks in food and feed safety. Regular updates of this Guidance are foreseen in light of experience and new evidence both in food and feed safety and systematic review methodology.