Multiple factors, including peripheral vascular disease and neuropathy, contribute to the development and perpetuation of complications of the lower extremities in diabetes. The main aim of the present study was to assess the peripheral vascular and nerve status of diabetic and non-diabetic subjects that had undergone lower limb amputation. Various non-invasive tests of peripheral vascular and nerve function were carried out on subjects who had undergone unilateral lower limb amputation and were now attending a Rehabilitation Centre. The control group (n=23), the diabetic amputee group (n=64) and the non-diabetic amputee group (n=32) were age-matched. Only the diabetic amputee group had evidence of medial arterial calcification. Transcutaneous oxygen levels were significantly lower in the diabetic amputee group (median 43 mmHg; interquartile range 33-49 mmHg) than in the control (59; 56-74 mmHg) and non-diabetic amputee (57; 43-65 mmHg) groups (control compared with diabetic amputee group, P<0.001; diabetic amputee compared with non-diabetic amputee group, P<0.01). The same trend was found for carbon dioxide levels in the skin [mmHg: diabetic amputees, 25 (21-37); controls, 38 (32-42); non-diabetic amputee, 34 (31-39)] (control compared with diabetic amputee, P<0.01; diabetic amputee compared with non-diabetic amputee, P<0.05). Vibration and pressure perception measurements (which assess Abeta nerve fibre function) showed that both the diabetic amputee and non-diabetic amputee subjects had significantly greater impairment than the controls. However, measures of Aalpha and C nerve fibre function were abnormal only in the diabetic amputee group. Thus the peripheral vascular and nerve functions of age-matched diabetic and non-diabetic subjects having undergone lower limb amputation show specific differences, with non-diabetic amputees exhibiting signs of neuropathy. This indicates that factors characteristic of diabetes (such as hyperglycaemia and non-enzymic glycation) are associated with calcification, lower oxygen and carbon dioxide levels in the skin, and abnormal Aalpha and C nerve fibre function.