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We defined the causal pathways responsible for 80 consecutive initial lower-extremity amputations to an extremity in diabetic patients at the Seattle Veterans Affairs Medical Center over a 30-mo interval from 1984 to 1987. Causal pathways, either unitary or composed of various combinations of seven potential causes (i.e., ischemia, infection, neuropathy, faulty wound healing, minor trauma, cutaneous ulceration, gangrene), were determined empirically after a synthesis by the investigators of various objective and subjective data. Estimates of the proportion of amputations that could be ascribed to each component cause were calculated. Twenty-three unique causal pathways to diabetic limb amputation were identified. Eight frequent constellations of component causes resulted in 73% of the amputations. Most pathways were composed of multiple causes, with only critical ischemia from acute arterial occlusions responsible for amputations as a singular cause. The causal sequence of minor trauma, cutaneous ulceration, and wound-healing failure applied to 72% of the amputations, often with the additional association of infection and gangrene. We specified precise criteria in the definition of causal pathway to permit estimation of the cumulative proportion of amputations due to various causes. Forty-six percent of the amputations were attributed to ischemia, 59% to infection, 61% to neuropathy, 81% to faulty wound healing, 84% to ulceration, 55% to gangrene, and 81% to initial minor trauma. An identifiable and potentially preventable pivotal event, in most cases an episode involving minor trauma that caused cutaneous injury, preceded 69 of 80 amputations. Defining causal pathways that predispose to diabetic limb amputation suggests practical interventions that may be effective in preventing diabetic limb loss.