: Despite advancements in vascular surgery, the mortality among peripheral arterial disease (PAD) patients undergoing major amputations remains high. While a large body of evidence has previously covered survival rates after major amputation, there is less evidence regarding the associated survival penalty from an epidemiological perspective. The present analysis aimed at quantifying the survival disadvantage after major lower limb amputation while investigating which factors are associated with mortality in this patient cohort. : Data from 246 PAD patients undergoing major amputations were retrospectively collected and matched with mortality records from the Austrian National Death Registry. Life expectancy was estimated using population-based life tables, and differences between observed and expected survival were analyzed across subgroups. : The median follow-up was 492 days (Q1-Q3: 73-1438), and 82.5% (n = 203) of patients died, with cardiovascular events being the leading cause (41%). A profound discrepancy between estimated (4697 days, Q1-Q3: 2962-6236) and observed survival (457 days, Q1-Q3: 73-1438, < 0.001) was seen. In men, an associated median survival penalty of 11.2 years was observed, equivalent to a proportionate reduction in life expectancy of over 90%, while the difference in women was 8.7 years, equaling a reduction of 84.6%. In a multiple regression model, 1 year in life expectancy was associated with a survival penalty of -0.96 years, thereby affecting younger patients with the highest life expectancies the most. : Major amputation in PAD patients is associated with a significant reduction in survival compared to standardized mortality rates in the general population. The survival disadvantage exceeds 70% of estimated survival times in over 70% of patients. Elevated mortality rates after major amputation in PAD patients should not be interpreted as a causal relationship but as a surrogate for impaired systemic cardiovascular health.

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