SENTIERI project (Epidemiological Study of Residents in Italian Contaminated Sites) studied mortality in the sites of national interest for environmental remediation (National Priority Contaminated Sites—NPCSs). SENTIERI described mortality of residents in NPCSSs, and it specifically focused on causes of death for which environmental exposure is suspected or ascertained to play an etiologic role. The epidemiological evidence of the causal association was classified a priori into one of these three categories: Sufficient (S), Limited (L), and Inadequate (I). Mortality in the period 1995−2002 was studied for 63 single or grouped causes at the municipal level by computing: crude rate, standardized rate, standardized mortality ratios (SMR), and SMR adjusted for an ad hoc deprivation index. Regional populations were used as references for SMR calculations and 90% CI accompanied SMR values. The deprivation index was constructed using 2001 national census variables for the following socioeconomic domains: education, unemployment, dwelling ownership, and overcrowding. SENTIERI results will allow the priorities setting in remediation intervention so as to prevent adverse health effects from environmental exposure. This paper's objective is to present the rationale, methods, advantages, and limitations underlying SENTIERI project and to describe data and resources required to apply a similar approach in other countries.