Addressing the spatio-temporal clusters of non-infectious diseases is complex and requires expertise in multiple fields: health, technical, economic, and social. In similar situations, investigations conducted to date have revealed a wide range of responses from scientific, health, and social perspectives, and thus an inequity in how the problem is addressed. The objective of this document is to serve as a reference methodological guide for healthcare professionals in health administrations, health agencies, and research institutes responsible for the health assessment of these events. Within this general framework, this guide aims to: - systematize the management of clusters and standardize investigations from the moment of reporting; - propose an appropriate public health response through: - listening to and understanding the public’s concerns; - the timeliness and transparency of the actions implemented; - involving the public or its representatives in the process; - formulating well-reasoned conclusions and providing substantiated justification for whether or not to undertake additional actions (assessment, management); - ensuring careful communication; - utilizing public health resources appropriately while avoiding the implementation of studies or investigations that are not scientifically justified. The guidelines proposed in this guide are based on a review of the literature on the subject and on experience gained during various investigations. They comprise structured recommendations that can be adapted to specific situations. The experience gained in the assessment and management of spatiotemporal clusters will allow these recommendations—which currently constitute a first edition—to evolve. This guide applies solely to spatio-temporal clusters of non-infectious diseases reported in the general population, with or without an initial environmental etiological hypothesis. Study methods designed to identify clusters based on routinely collected morbidity or mortality data across a large geographic area (clustering) are excluded from this guide. (R.A.)