CONTEXT: No study analysed the prevalence of white matter hyperintesities (WMHs) in subjects with diabetic foot syndrome (DFS) and their relationship with adipokine serum levels and indexes of endothelial and cognitive performance. OBJECTIVE: To evaluate omentin and vaspin serum levels and WMHs prevalence in subjects with DFS and to analyse their relationship with other endothelial, arterial stiffness and cognitive function. RESEARCH DESIGN AND METHODS: Case-control study enrolling 40 subjects with DFS, 40 diabetic subjects without foot complications, 40 controls with foot lesions without diabetes and 40 patients without diabetes mellitus. MAIN OUTCOME MEASURE: Pulse wave velocity (PWV), augmentation index (Aix), Reactive hyperemia index (RHI), serum vaspin and omentin levels, Fazekas Score, MMSE. RESULTS: Subjects with DFS showed higher mean PWV values if compared with diabetic controls, lower RHI values if compared with controls. They also showed a lower mean MMSE score, significantly lower omentin serum levels, a higher prevalence of grade 2 severity of periventricular hyperintensities (PVH). We observed a significant positive correlation between PWV and PVH, between Fazekas Score and PWV among diabetic subjects, whereas among subjects with diabetic foot we observed a significant negative correlation between PVH and RHI. CONCLUSIONS: Diabetes seems to be more associated with endothelial function disturbance in comparison with patients with diabetic foot that exhibit a more strict association with microvascular brain damage as indicated by our significant finding of an association with periventricular hyperintensities.