The association between BMI and amputation risk is not currently well known. We used data for a cohort of diabetic patients treated in the US Department of Veterans Affairs Healthcare System in 2003. Men aged <65 years at the end of follow-up were examined for their amputation risk and amputation-free survival during the next 5 years (2004-2008). Compared to overweight individuals (BMI 25-29.9 kg/m(2)), the risks of amputation and treatment failure (amputation or death) were higher for patients with BMI <25 kg/m(2) and were lower for those with BMI ≥30 kg/m(2). Individuals with BMI ≥40 kg/m(2) were only half as likely to experience any (hazard ratios (HR) = 0.49; 95% confidence interval (CI), 0.30-0.80) and major amputations (HR = 0.53; 95% CI, 0.39-0.73) during follow-up as overweight individuals. While the amputation risk continued to decrease for higher BMI, amputation-free survival showed a slight upturn at BMI >40 kg/m(2). The association between obesity and amputation risk in our data shows a pattern consistent with "obesity paradox" observed in many health conditions. More research is needed to better understand pathophysiological mechanisms that may explain the paradoxical association between obesity and lower-extremity amputation (LEA) risk.