Costs of cancer care are increasing worldwide, and sustainability of cancer burden is critical. In this study, the economic impact of rectal cancer on the Italian healthcare system, measured as public healthcare expenditure related to investigation and treatment of rectal cancer patients is estimated. A cross-sectional cohort of 9358 rectal cancer patients is linked, on an individual basis, to claims associated to rectal cancer diagnosis and treatments. Costs refer mainly to years 2010–2011 and are estimated by phase of care, as healthcare needs vary along the care pathway: diagnostic procedures are mainly provided in the first year, surveillance procedures are addressed to chronically ill patients, and end-of-life procedures are given in the terminal status. Clinical approaches and corresponding costs are specific by cancer type and vary by phase of care, stage at diagnosis, and age. Surgery is undertaken by the great majority of patients. Thus, hospitalization is the main cost driver. The evidence produced can be used to improve planning and allocation of healthcare resources. In particular, early diagnosis of rectal cancer is a gain in healthcare budget. Policies raising spreading of and adherence to screening plans, above all when addressed to people living in Southern Italy, should be strongly encouraged.