Imiquimod (Aldara) is a topical immune response modifier effective against a variety of cutaneous tumors. Post therapy histologic reaction patterns have not been well characterized. Here, we present 2 patients treated with imiquimod, whose biopsies showed interface dermatitis of the epidermis and the adnexae with prominent periadnexal and perivascular lymphocytic inflammation. Without the clinical history, these histologic findings may be misinterpreted as lupus erythematosus. This report describes a new finding in imiquimod-treated skin and supports the diversity of reaction patterns that may be seen in association with imiquimod treatment.