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The mainstay of treatment of chronic venous ulceration (CVU), as also suggested by current treatment guidelines for chronic venous disease (CVD), is represented by surgery and compression therapy for which there is strong evidence of their role in clinically relevant improvement in wound healing and also in the reduction of CVU recurrence, but no information is available as to whether or not these treatments provide effective protection from the onset of CVU. In our study, we have followed, for a median time of 13 years, a total of 3947 patients with CVD at classes C2–C3 of CEAP classification, treated with our treatment protocol (surgery and compression therapy) in order to track the natural history of these patients with regards to CVU development. We identified four groups of patients: 2354 patients (59·64%) (Group A) fully adherent to protocols; 848 patients (21·48%) (Group B) fully adherent to surgery and non-compliant to compression therapy; 432 patients (10·95%) (Group C) fully adherent to compression therapy and non-compliant to surgery; and 313 patients (7·93%) (Group D) non-compliant to either treatments. Regardless of compliance to treatments, the ulcer development rates were very similar between groups (range: 3·23–4.79%), with no statistical significance (P = 0·1522). Currents treatments used in the early stages of CVD appear to have no effects to progression to CVU. Additional longitudinal studies are required to confirm these findings.