The Seveso accident in 1976 caused a large, populated area north of Milan, Italy, to be contaminated by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). In this study, the authors followed up the exposed population for chronic effects; this paper reports the results of the mortality follow-up extension for 1997–2001. The study cohort includes 278,108 subjects resident at the time of the accident or immigrating/born in the 10 years thereafter in three contaminated zones with decreasing TCDD soil levels (zone A, very high; zone B, high; zone R, low) and in a reference territory comprising surrounding, noncontaminated municipalities. Vital status and cause-of-death ascertainment were 99% complete. Adjusted rate ratios and 95% confidence intervals were calculated by using Poisson regression. Results confirmed previous findings of excesses of lymphatic and hematopoietic tissue neoplasms in zones A (six deaths; rate ratio = 2.23, 95% confidence interval: 1.00, 4.97) and B (28 deaths; rate ratio = 1.59, 95% confidence interval: 1.09, 2.33). These zones also showed increased mortality from circulatory diseases in the first years after the accident, from chronic obstructive pulmonary disease, and from diabetes mellitus among females. A toxic and carcinogenic risk to humans after high TCDD exposure is supported by the results of this study.