Few large studies on Northern European or US populations reported on mortality of severely obese individuals (BMI ≥ 40 kg/m2). We studied a historical cohort in Italy to compare its mortality with previous findings, to investigate its relationship with BMI in the >40 range, and to provide evidence useful for clinical decision-making on treatment. The cohort comprised 4,837 persons with a BMI ≥40 kg/m2 and aged ≥18 at first consultation, referred to six centers for obesity treatment between 1975 and 1996. After exclusion of persons with missing personal identification data or those untraceable, 4,498 (972 men, 3,526 women) remained for analyses. We calculated standardized mortality ratios (SMRs) and carried out Cox proportional hazards modeling. General mortality (484 deaths: 153 men, 331 women) was in excess, with SMRs (95% confidence intervals) of 2.78 (2.36–3.26) for men and 2.10 (1.88–2.34) for women. Excess mortality (i) was observed in all BMI categories, except among women weighing 40–42.4 kg/m2; (ii) increased with increasing BMI; (iii) increased less among persons recruited in recent calendar periods; (iv) was inversely related to age attained at follow-up; and (v) was due to cardiovascular and respiratory diseases and violent deaths but not malignant neoplasms. Excess mortality was similar to that observed in Northern European and US cohorts. Its steady increase with BMI levels ≥40 suggests that benefits proportional to weight reduction are expected and that even limited control may be beneficial. The smaller excess among persons recruited most recently might reflect better treatment.