OBJECTIVE To assess the efficacy of insulin plus sulodexide (a mixture of 80% heparin-like substances and 20% dermatan sulphate) on diabetic ulcers, and its influence on foot skin microcirculation and diabetic neuropathy. RESEARCH DESIGN AND METHODS Two groups of diabetic patients, suffering from severe neuropathy and ulceration, were randomly assigned to insulin (I) plus sulodexide (S) (n=12) or insulin plus placebo (P) (n=6) therapy, for 10 weeks. Laser Doppler assessment of foot skin flow (LDF), at rest and 30 or 60 s after arterial occlusion, and nerve conduction tests (sensorial evoked and motoric conduction potentials) have been evaluated in both groups. RESULTS Postischaemic flow was 2.5 times shorter in ulcerated vs. non-ulcerated feet in diabetic patients. A significant increase in flows after 30 and 60 s ischaemia was detected in both groups at the end of therapy (IS group, ulcerated foot, LDF=60 s: from 99.1+/-14.3 to 218.6+/-28.6 PU, P<.001. IP group=from 110.5+/-13.0 to 164.8+/-15.4 PU, P<.05). The length of reactive hyperaemia was higher in IS vs. IP group (IS: from 30.3+/-2.9 to 43.9+/-2.2 s, P<.001; IP: from 28.7+/-3.0 to 33.3+/-3.3 s, ns). Ninety-two percent of ulcers heals in a mean time of 46.4 days (IS group) vs. 83% and 63.0 days, respectively, in IP group. Nerve conduction studies have not demonstrated within- and between-group differences. CONCLUSIONS Sulodexide and insulin improve the postischaemic skin flow in ulcerated feet, without affecting nerve conduction tests. The effect of sulodexide results additive to insulin; it is clinically relevant, in the view of the possibility of reducing the time needed to completely heal ulcers. The ultimate validation of these preliminary results requires extensive trials.