Hydroxyurea (HU) is an antitumor agent effective in the treatment of myeloproliferative disorders. It is usually well-tolerated and has low toxicity but its use is associated with several adverse cutaneous effects. Among them, leg ulcers have been noted in association with long-term administration. Poor response to traditional local and systemic therapy is a typical feature of HU-induced leg ulcers, and discontinuation of the drug is often required to achieve complete wound healing. We present a case of circumferential HU-induced leg ulcer in a patient affected by essential thrombocythemia, in which the lesion occured after the definitive suspension of the treatment. We propose a conservative management with a new collagenase (Bionect Start®) for skin lesions in this type of patient, for whom a surgical treatment could be more complicated, due to the underlying disease.