Therapeutic strategy for treating cryoglobulinemic cutaneous ulcers should be based on both systemic and local treatments. After clinical work-up considering the entire MCs, including possible comorbidities (venous insufficiency and/or arteriosclerotic alterations, diabetes, and so on), and careful examination of the ulcer characteristics, the systemic treatment may be based on etiological, pathogenetic, and/ or symptomatic therapies. More aggressive combined treatments (immunosuppressors, steroids, and plasmapheresis) may be necessary in the presence of very severe, non-healing skin ulcers. Long-term administration of analgesics is often necessary to improve the patient's chronic pain and compliance with local treatment, which should be carried out at a wound care clinic. Wound bed preparation, with particular regard to the prevention and treatment of infections, is crucial for the healing of cryoglobulinemic skin ulcers. CPX, cyclophosphamide; peg-IFN, peg-interferon; RIBA, ribavirin; RTX, rituximab.