OBJECTIVE: To determine the mortality rate after diabetes-related lower-extremity amputation (LEA) in an African-descent Caribbean population. RESEARCH DESIGN AND METHODS: We conducted a prospective case-control study. We recruited case subjects (with diabetes and LEA) and age-matched control subjects (with diabetes and no LEA) between 1999 and 2001. We followed these groups for 5 years to assess mortality risk and causes. RESULTS: There were 205 amputations (123 minor and 82 major). The 1-year and 5-year survival rates were 69 and 44% among case subjects and 97 and 82% among control subjects (case-control difference, P < 0.001). The mortality rates (per 1,000 person-years) were 273.9 (95% CI 207.1-362.3) after a major amputation, 113.4 (85.2-150.9) after a minor amputation, and 36.4 (25.6-51.8) among control subjects. Sepsis and cardiac disease were the most common causes of death. CONCLUSIONS: These mortality rates are the highest reported worldwide. Interventions to limit sepsis and complications from cardiac disease offer a huge potential for improving post-LEA survival in this vulnerable group.