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The number of hemodialysis patients with peripheral artery disease is increasing, and critical limb ischemia develops in some of these patients. The clinical outcomes in such patients after major amputation remain unclear. We therefore examined the mortality rates after major amputation in hemodialysis patients.The study enrolled 108 hemodialysis patients undergoing their first major amputation at Community Health Care Organization Sendai Hospital between January 2005 and December 2014 and monitored them until June 2015. All-cause mortality and additional amputation-free survival were evaluated by Kaplan-Meier analysis.The most dominant primary disease of renal failure was diabetes mellitus (77%), and the duration of hemodialysis was 8.5 ± 6.8 years. During the median follow-up period of 11.5 months (20.3 ± 22.6 months), 80 patients (74%) died, and the survival rates were 83% at 30 days, 56% at 1 year, and 15% at 5 years. The median time to death was 19.9 months (95% confidence interval, 9.8-30.0 months), and the causes of death were cardiac (45%), sepsis (29%), cerebrovascular (4%), and others (22%). Thirty-one patients underwent additional amputation, and the additional amputation-free survival rates were 39% at 1 year and 9% at 5 years. The median time between the first and second amputations was 2.5 months (5.7 ± 7.6 months). Univariate analysis showed previous minor amputation (P= .04) and low hematocrit level (P= .04) were associated with the 30-day mortality rate, and age (P= .05) was associated with the 5-year mortality rate. On multivariate Cox proportional hazard analysis, only age was associated with mortality rate (hazard ratio, 1.02; 95% confidence interval, 0.99-1.02;P= .04). We also compared walking ability before and after major amputation among patients who survived >60 days. The rate changed from 34% to 12% for of ambulatory patients, from 45% to 48% for wheelchair use, and from 21% to 40% for bedridden patients. Ambulatory patients had a significantly better survival rate than the others (P= .02).The mortality rate after major amputation in hemodialysis patients was high, and major amputation had a huge negative effect on patients' walking ability.