Background Marked changes in the prevalence of noncommunicable diseases such as obesity, diabetes, and cardiovascular disease have occurred in developed and developing countries in recent decades. The overarching aim of the study is to examine the relationship of societal influences on human lifestyle behaviors, cardiovascular risk factors, and incidence of chronic noncommunicable diseases. Methods The Prospective Urban Rural Epidemiology (PURE) study is a large-scale epidemiological study that plans to recruit approximately 140,000 individuals residing in N600 communities in 17 low-, middle-, and high-income countries around the world. Individual data collection includes medical history, lifestyle behaviors (physical activity and dietary profile), blood collection and storage for biochemistry and future genetic analysis, electrocardiogram, and anthropometric measures. In addition, detailed information is being collected with respect to 4 environmental domains of interest-the built environment, nutrition and associated food policy, psychosocial/socioeconomic factors, and tobacco environment. A minimum follow-up of 10 years is currently planned. Results This report describes the design, justification, and methodology of the PURE study. The PURE study has been recruiting since 2002 and has enrolled 139,506 individuals by March 31, 2009. Conclusions The PURE study builds on the work and experience gained through conduct of the INTERHEART study. Its design and extensive data collection are geared toward addressing major questions on causation and development of the underlying determinants of cardiovascular disease in populations at varying stages of epidemiologic transition.