The National Environmental Remediation programme in Italy includes sites with documented contamination and associated potential health impacts (National Priority Contaminated Sites-NPCSs). SENTIERI Project, an extensive investigation of mortality in 44 NPCSs, considered the area of Taranto, a NPCS where a number of polluting sources are present. Health indicators available at municipality level were analyzed, that is, mortality (2003-2009), mortality time trend (1980-2008), and cancer incidence (2006-2007). In addition, the cohort of individuals living in the area was followed up to evaluate mortality (1998-2008) and morbidity (1998-2010) by district of residence. The results of the study consistently showed excess risks for a number of causes of death in both genders, among them: all causes, all cancers, lung cancer, and cardiovascular and respiratory diseases, both acute and chronic. An increased infant mortality was also observed from the time trends analysis. Mortality/morbidity excesses were detected in residents living in districts near the industrial area, for several disorders including cancer, cardiovascular, and respiratory diseases. These coherent findings from different epidemiological approaches corroborate the need to promptly proceed with environmental cleanup interventions. Most diseases showing an increase in Taranto NPCS have a multifactorial etiology, and preventive measures of proven efficacy (e.g., smoking cessation and cardiovascular risk reduction programs, breast cancer screening) should be planned. The study results and public health actions are to be communicated objectively and transparently so that a climate of confidence and trust between citizens and public institutions is maintained.