OBJECTIVE—The pathogenesis of painful diabetic neuropathy (PDN) is not clear. Following our in vivo observations of increased sural nerve epineurial blood flow in patients with PDN, we investigated the cutaneous microcirculation of the foot by laser Doppler flowmetry to determine if the epineurial findings were just confined to the nerve or more widespread in other vascular beds. RESEARCH DESIGN AND METHODS—We measured foot skin vasodilator responses to acetylcholine (Ach) and sodium nitroprusside (SNP) and vasoconstrictor responses to sympathetic (deepest possible gasp) stimulation in 5 healthy control subjects, 10 non-neuropathic diabetic (NND) patients, 10 diabetic patients with painless neuropathy (PLDN), and 8 diabetic patients with PDN. RESULTS—In PDN, there were significantly reduced responses to Ach (ANOVA P = 0.003) and vasoconstrictor inspiratory gasp (ANOVA P < 0.001) but not to SNP (NS). Post hoc analysis showed significant differences in Ach-induced vasodilation between PDN and nondiabetic control subjects (P < 0.05) as well as between PDN and NND (P < 0.05) but not PDN and PLDN (NS). There were no significant differences for SNP-induced vasodilation. However, there were significant differences in the vasoconstrictor response between PDN and control, NND, and PLDN (P < 0.01). CONCLUSIONS—We found an impairment of cutaneous endothelium-related vasodilation and C-fiber–mediated vasoconstriction in PDN. Inappropriate local blood flow regulation may have a role in the pathogenesis of pain in diabetic neuropathy. Prospective studies are required to determine the temporal relationship of these changes in relation to the emergence of neuropathic pain.