The application of environmental performance indicators (EPIs) has received increasing attention by both governments and international organisations as a tool for assessing complex environmental scenarios in national and local decision making processes. However, at the regional scale there is a gap in the application of EPIs, as this has not been well understood and defined due to a limited theoretical foundation and often insufficient data from all participant countries. The regional scale is important because it can incorporate natural ecosystems which often transcend national boundaries. A case study is developed for the Lower Mekong Subregion (LMS), where four riparian Southeast Asian countries (Lao PDR, Thailand, Cambodia, and Viet Nam) share the Lower Mekong River. The research proposes a conceptual framework to identify approaches for developing criteria for acceptable and appropriate EPIs which can be used to support and implement decision making processes by relevant organisations at the regional level. This research evaluates the application of environmental performance indicators using methodologies that assess cross-national quantitative and qualitative data and existing decision support systems. In addition, global and national indicators are examined for application and relation to the regional context. The research finds that the application of EPIs varies according to spatial scale, and is diverse among the four countries. Data availability is also identified as a major problem encountered during the development and selection of EPIs. The study finds that the governance of the existing regional body is ineffective due to differing agendas pursued by each participating country. This is because the current regional body is structured only to facilitate information exchange and cooperation in a limited manner, focusing so far only on water management issues. LMS regional goals need to be set in order to guide the stakeholders in identifying an appropriate set of EPIs. Most importantly, the research is intended to be a catalyst for encouraging the participants to integrate methods and other species of EPIs proposed in this research in their environmental assessment policies.