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Primary cutaneous marginal zone lymphomas (pcMZL) belong to the primary cutaneous B-cell lymphoma (pCBCL) group. They are characterized by their restriction to the skin and a high likelihood of recurrence after various treatment modalities. First-line therapy consists of surgery and radiotherapy. These therapies may not always be indicated in young patients or in patients with pCBCL located in the face, where surgery or radiotherapy may leave disfiguring scars or radioderma. Eight patients with pcMZL were treated with intra-lesional injections of 3 million units of recombinant IFNalpha2a three times per week. The patients either did not want to undergo or did not qualify for surgical excision or radiotherapy due to inappropriate localization or age. All patients experienced complete tumor regression after a mean of 8.5 weeks (range 3 - 20). Two patients relapsed 4 and 12 months after treatment, respectively, but tumor regression was repeated after additional cycles of intra-lesional IFNalpha2a. All other patients remained free of disease. Thus, intra-lesional IFNalpha2a may represent a valuable alternative to surgery and radiotherapy as first-line treatment of pcMZL.